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UBC Theses and Dissertations

The potential use of radioiodinated fatty acids as myocardial imaging agents Chung, Connie Joan 1979

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THE POTENTIAL USE OF RADIOIODINATED FATTY ACIDS AS MYOCARDIAL IMAGING AGENTS BY C o n n i e J o a n Chung B . S c . ( P h a r m . ) U n i v e r s i t y o f B r i t i s h C o l u m b i a , 1974 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n THE FACULTY OF GRADUATE STUDIES , D i v i s i o n o f P h a r m a c e u t i c a l C h e m i s t r y , i n The F a c u l t y o f P h a r m a c e u t i c a l S c i e n c e s We a c c e p t t h i s t h e s i s as c o n f o r m i n g t o t h e r e q u i r e d s t a n d a r d THE UNIVERSITY OF B R I T I S H COLUMBIA M a r c h , 1979 (c} C o n n i e J o a n C h u n g , 1979 I n p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r a n a d v a n c e d d e g r e e a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e a n d s t u d y . I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d by t h e Head o f my D e p a r t m e n t o r by h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . D e p a r t m e n t nf tffanMvilMtuhJ JL JlfAo^tot The U n i v e r s i t y o f B r i t i s h C o l u m b i a 2075 W e s b r o o k P l a c e V a n c o u v e r , C a n a d a V6T 1W5 D a t e JI^JSpX i i ABSTRACT The p o t e n t i a l u s e o f f o u r r a d i o i o d i n a t e d f a t t y a c i d s a s m y o c a r d i a l i m a g i n g a g e n t s w e r e e v a l u a t e d . P r e l i m i n a r y d i s t r i b u t i o n s t u d i e s r e v e a l e d t h a t t h e t e r m i n a l l a b e l e d f a t t y a c i d s d e m o n s t r a t e d h i g h e r m y o c a r d i a l u p t a k e . T h u s , 1 0 - I o d o c a p r i c a c i d ( 1 0 - i o d o d e c a n o i c ) and 1 2 - I o d o l a u r i c a c i d w e r e s u b j e c t e d t o f u r t h e r i n v e s t i g a t i o n . C o m p r e h e n s i v e t i s s u e d i s t r i b u t i o n s t u d i e s i n v o l v i n g b o t h r a d i o i o d i n a t e d f a t t y a c i d s i n m i c e i n d i c a t e d t h a t t h e h i g h e s t a c c u m u l a t i o n o f t h e t o t a l i n j e c t e d a c t i v i t y o c c u r r e d i n t h e m u s c l e a n d t h e b l o o d . O t h e r o r g a n s i n v e s t i g a t e d i n c l u d e d t h e h e a r t , l i v e r , l u n g , k i d n e y s , s p l e e n , s t o m a c h , i n t e s t i n e s , b o n e a n d a d r e n a l s . The h e a r t e x h i b i t e d t h e h i g h e s t c o n c e n t r a t i o n o f t h e r a d i o i o d i n a t e d f a t t y a c i d s f o r t h e r e l a t i v e a c c u m u l a t i o n o f a c t i v i t y p e r u n i t w e i g h t . Erom t h e t i s s u e d i s t r i b u t i o n s t u d i e s , t h e o p t i m u m s c a n n i n g t i m e was f o u n d t o be i m m e d i a t e l y f o l l o w i n g i n j e c t i o n o f t h e r a d i o p h a r m a c e u t i c a l . T o x i c i t y s t u d i e s w e r e p e r f o r m e d i n m i c e a f t e r i n t r a v e n o u s a d m i n i s t r a t i o n o f 1 0 - B r o m o c a p r i c a c i d a n d 1 2 - B r o m o l a u r i c a c i d . The LDrn o f S o d i u m B r o m o l a u r a t e i n 10% Human S e r u m A l b u m i n was f o u n d t o 50 be 210 m g / k g ( 1 9 4 m g / k g - 228 m g / k g ) . The s t a b i l i t y p r o b l e m e n c o u n t e r e d w i t h 1 0 - B r o m o c a p r i c a c i d n e c e s s i t a t e d t h e u s e o f a d i f f e r e n t s o l v e n t s y s t e m . The L D 5 0 o b t a i n e d a f t e r i n t r a v e n o u s i n j e c t i o n was f o u n d t o be 8 6 . 1 m g / k g ( 8 3 . 0 mg/kg - 8 9 . 3 m g / k g ) . H o w e v e r , t h i s o b s e r v e d t o x i c i t y may n o t n e c e s s a r i l y r e f l e c t t h e t o x i c i t y o f t h e B r o m o c a p r i c a c i d s o l e l y . i i i W h o l e b o d y e x c r e t i o n s t u d i e s w e r e p e r f o r m e d i n m i c e a n d r e v e a l e d a t r i e x p o n e n t i a l e x c r e t i o n c u r v e . F o r 1 0 - I o d o c a p r i c a c i d , t h e e f f e c t i v e h a l f - l i v e s w e r e . 9 0 h o u r s ( 3 6 . 7 % ) , 3 . 9 1 h o u r s ( 6 1 . 6 % ) a n d 7 4 . 9 h o u r s ( 1 4 . 5 % ) . F o r 1 2 - I o d o l a u r i c a c i d , t h e e f f e c t i v e h a l f -l i v e s w e r e 1 . 6 7 h o u r s ( 4 6 . 6 % ) , 7 . 6 8 h o u r s ( 3 8 . 4 % ) , a n d 7 1 . 6 h o u r s ( 1 7 . 8 % ) . F o r b o t h 1 0 - I o d o c a p r i c a c i d a n d 1 2 - I o d o l a u r i c a c i d , t h e f i r s t a s w e l l a s t h e s e c o n d c o m p o n e n t o f t h e e x c r e t i o n c u r v e p r e s u m a b l y r e p r e s e n t e d a d e c r e a s e i n t h e w h o l e b o d y a c t i v i t y due m a i n l y t o u r i n a r y e x c r e t i o n . The t h i r d c o m p o n e n t a p p e a r e d t o r e p r e s e n t a c t i v i t y w h i c h was t i g h t l y b o u n d a n d s l o w l y r e l e a s e d . The t h i r d c o m p o n e n t p r e s u m a b l y r e p r e s e n t e d e l i m i n a t i o n by f e c a l e x c r e t i o n . The e x c r e t i o n o f t h e i n j e c t e d a c t i v i t y was p r i m a r i l y i n t h e u r i n e , a l t h o u g h some a c t i v i t y was r e c o v e r e d i n t h e f e c e s . F o r 1 0 - I o d o c a p r i c a c i d , 8 2 . 4 % o f t h e i n j e c t e d a c t i v i t y h a d b e e n r e c o v e r e d i n t h e u r i n e w i t h i n t h e f i r s t 24 h o u r s a n d 8 . 8 8 % had b e e n r e c o v e r e d i n t h e f e c e s . F o r 1 2 - I o d o l a u r i c a c i d , 7 8 . 9 % o f t h e i n j e c t e d d o s e was r e c o v e r e d i n t h e u r i n e a t 24 h o u r s a n d 9 . 4 % i n t h e f e c e s . From t h e u r i n e r e s u l t s , t h e e f f e c t i v e h a l f - l i f e o f t h e r a d i o -i o d i n a t e d f a t t y a c i d s i n t h e k i d n e y s was f o u n d t o be 4 . 8 h o u r s . 131 M y o c a r d i a l s c a n s w e r e done on r a b b i t s u s i n g I - c a p r i c a c i d , 131 I - l a u r i c a c i d , N a I - 1 3 1 (6% Human S e r u m A l b u m i n ) , a n d T h a l l i u m - 2 0 1 a t s p e c i f i e d t i m e i n t e r v a l s a f t e r i n j e c t i o n . I o d i n e - 1 2 3 , a r a d i o n u c l i d e p o s s e s s i n g more f a v o r a b l e i m a g i n g p r o p e r t i e s , was n o t r e a d i l y a v a i l a b l e due t o p r o d u c t i o n p r o b l e m s a t t h e t i m e o f s c a n n i n g . The mean a b s o r b e d d o s e t o t h e w h o l e b o d y , t h e l i v e r , t h e k i d n e y s , t h e m u s c l e , a n d t h e h e a r t w e r e c o m p u t e d b a s e d on t h e r e s u l t s f r o m t h e i v d i s t r i b u t i o n a n d e x c r e t i o n s t u d i e s . The d o s i m e t r y c a l c u l a t i o n s 123 w e r e d o n e u s i n g I o d i n e - 1 2 3 a s t h e r a d i o n u c l i d e . F o r I - c a p n c a c i d , t h e r a d i a t i o n d o s e s w e r e c a l c u l a t e d a s 3 4 . 7 6 mr?ads/2 mCi f o r t h e w h o l e b o d y , 1 3 6 . 3 m r a d s / 2 mCi f o r t h e k i d n e y s , 8 6 . 6 m r a d s / 2 mCi f o r t h e l i v e r , 3 8 . 5 m r a d s / 2 mCi f o r t h e m u s c l e , a n d 2 5 . 8 9 m r a d s / 2 mCi 123 f o r t h e h e a r t . F o r I - l a u r i c a c i d , t h e r a d i a t i o n d o s e s w e r e 4 1 . 7 3 m r a d s / 2 mCi f o r t h e w h o l e b o d y , 1 9 9 . 8 m r a d s / 2 mCi f o r t h e k i d n e y s , 1 8 5 . 9 m r a d s / 2 mCi f o r t h e l i v e r , 5 2 . 0 7 m r a d s / 2 mCi f o r t h e m u s c l e , a n d 4 6 . 3 9 m r a d s / 2 mCi f o r t h e h e a r t . S u p e r v i s o r i V TABLE OF CONTENTS P a g e A b s t r a c t i i T a b l e o f C o n t e n t s v L i s t o f T a b l e s x i •:' L i s t o f F i g u r e s x i i ' i • A c k n o w l e d g e m e n t s X V 1 , I . INTRODUCTION 1 I I . LITERATURE SURVEY 8 1 . M y o c a r d i a l E n e r g e t i c s . . . 8 a ) A c u t e R e s p o n s e t o I s c h e m i a a n d I n f a r c t i o n . . 8 b) M o r p h o l o g i c a l F e a t u r e s o f A c u t e M y o c a r d i a l I n f a r c t i o n 9 c ) M i t o c h o n d r i a l C h a n g e s 10 2 . P o s i t i v e I n f a r c t - I m a g i n g A g e n t s 11 a ) G a l l i u m - 6 7 12 b) M e r c u r y - 2 0 3 13 c ) T e c h n e t i u m - 9 9 m C h e l a t e s 14 ( i ) Q ^ T c - t e t r a c y c l i n e 14 ( i i ) 9 9 m T c - g l u c o h e p t o n a t e 17 ( i i i ) 9 9 m T c - p y r o p h o s p h a t e m • 18 3 . N e g a t i v e I n f a r c t - I m a g i n g A g e n t s 20 a) P o t a s s i um 21 b) R u b i d i u m 24 c ) C e s i u m 26 d ) T h a l l i u m 2 8 e ) R a d i o i o d i n a t e d F a t t y a c i d s 32 f ) F u t u r e T r e n d s 32 ( i ) 13N-ammoni a • 32 ( i i ) n c - p a l m i t a t e and 11 C - o c t a n o a t e . . . . 34 v i TABLE OF CONTENTS ( C o n t d . ) P a g e 4 . F a t t y A c i d s 34 a) M y o c a r d i a l M e t a b o l i s m 36 ( i ) P e n e t r a t i o n o f P l a s m a F r e e F a t t y A c i d s i n t o C e l l s 37 b) M y o c a r d i a l E x t r a c t i o n 38 ( i ) The C i r c u l a t i n g FFA C o n c e n t r a t i o n . . . 39 ( i i ) The M o l a r R a t i o o f F F A / A l b u m i n . . . . 39 ( i i i ) C h a i n L e n g t h a n d t h e D e g r e e o f U n s a t u r a t i o n 4 0 c ) The U t i l i z a t i o n o f I n t r a c e l l u l a r F r e e F a t t y A c i d 43 d) . C a r n i t i n e 44 e ) O x i d a t i o n o f F a t t y A c i d s 45 ( i ) B e t a O x i d a t i o n 46 ( i i ) A l p h a O x i d a t i o n 46 ( i i i ) Omega O x i d a t i o n 4 8 f ) M y o c a r d i a l M e t a b o l i s m i n A c u t e M y o c a r d i a l I n f a r c t i o n 4 8 5 . I o d i n e - 1 2 3 49 6 . R a d i o i o d i n a t e d F a t t y A c i d s 50 I I I . EXPERIMENTAL METHODS AND MATERIALS 57 1 . A p p a r a t u s . 57 a) R e f l u x A s s e m b l y 57 b ) A u t o m a t e d Gamma C o u n t e r - 1 1 8 5 57 c ) T u b o r #8725 5 8 d) U n i - m e l t C a p i l l a r y M e l t i n g P o i n t A p p a r a t u s . 58 e ) C h r o m a t o g r a p h y Tank 58 f ) Gamma Camera 59 v i i TABLE OF CONTENTS ( C o n t d . ) Page 2 . C h e m i c a l s and R e a g e n t s 59 3 . F a t t y A c i d A n a l y s i s 62 a ) P u r i t y o f t h e B r o m i n a t e d F a t t y A c i d A n a l o g s . 62 ( i ) M e l t i n g P o i n t s 62 ( i i ) T h i n L a y e r C h r o m a t o g r a p h y ( T L C ) . . . . 62 b) P r e p a r a t i o n o f R a d i o i o d i n a t e d F a t t y A c i d s . . 6 3 ( i ) 9 - I o d o t e t r a d e c a n o i c A c i d 6 3 ( i i ) 2 - I o d o t e t r a d e c a n o i c A c i d , 1 0 - I o d o c a p r i c A c i d , and 1 2 - I o d o l a u r i c A c i d . . . . . 6 3 c ) A n a l y s i s o f R a d i o c h e m i c a l Y i e l d 64 d) P r e p a r a t i o n o f t h e R a d i o i o d i n a t e d F a t t y A c i d - A l b u m i n S o l u t i o n 64 e ) Removal o f F r e e I o d i d e - 1 3 1 65 f ) A n a l y s i s o f t h e S t a b i l i t y o f t h e R a d i o -i o d i n a t e d F a t t y A c i d i n 6% Human Serum A l b u m i n 5 5 o 4 . A n i m a l s 65 a ) M i c e 65 b ) R a b b i t s 66 5 . T i s s u e D i s t r i b u t i o n S t u d i e s . 66 6 . T o x i c i t y S t u d i e s 6 8 a) P r e p a r a t i o n o f S o d i u m B r o m o l a u r a t e . . . 68 b ) P r e p a r a t i o n o f B r o m o c a p r i c A c i d S o l u t i o n 69 7 . W h o l e Body E x c r e t i o n 69 8 . C o m p a r t m e n t a l A n a l y s i s 70 9 . E x c r e t i o n A n a l y s i s 70 " 1 0 . The R a d i o n u c l i d e S c a n 72 v i i i TABLE OF CONTENTS ( C o n t d . ) P a g e I V . RESULTS AND DISCUSSIONS 73 1 . A n a l y s i s o f t h e B r o m i n a t e d F a t t y A c i d A n a l o g s . . 73 a) M e l t i n g P o i n t s o f t h e B r o m i n a t e d F a t t y A c i d A n a l o g s 7 3 b) C h r o m a t o g r a p h y o f t h e B r o m i n a t e d F a t t y A c i d A n a l o g s and t h e P h y s i o l o g i c F a t t y A c i d s 74 2 . The R a d i o i o d i n a t i o n P r o c e d u r e s 76 a) 9 - I o d o t e t r a d e c a n o i c A c i d 76 b ) 2 - I o d o t e t r a d e c a n o i c A c i d , 1 0 - I o d o c a p r i c A c i d , a n d 1 2 - I o d o l a u r i c A c i d . . . . . . . . 76 c ) O p t i m i z a t i o n o f t h e R a d i o i o d i n a t i o n P r o c e d u r e s 77 ( i ) R a d i o c h e m i c a l Y i e l d s o f R a d i o i o d i n a t e d F a t t y A c i d s i n t h e A b s e n c e o f H e a t . . . 77 ( i i ) R a d i o c h e m i c a l Y i e l d s o f R a d i o i o d i n a t e d F a t t y A c i d s i n t h e P r e s e n c e o f H e a t . . 77 ( i i i ) R a d i o c h e m i c a l Y i e l d s o f R a d i o i o d i n a t e d F a t t y A c i d s U s i n g V a r i a b l e Q u a n t i t i e s o f B r o m i n a t e d F a t t y A c i d s a n d N a I - 1 3 1 . . 79 d) A n a l y s i s o f t h e S t a b i l i t y o f t h e R a d i o -i o d i n a t e d F a t t y A c i d s i n 6% Human S e r u m A l b u m i n 80 3 . P r e l i m i n a r y D i s t r i b u t i o n S t u d i e s o f 1 0 - I o d o -c a p r i c , 1 2 - I o d o l a u r i c , and 2 - I o d o t e t r a d e c a n o i c A c i d s 82 a ) P r e l i m i n a r y R a d i o n u c l i d e S c a n 84 4 . T i s s u e D i s t r i b u t i o n 87 a) 1 3 1 I - C a p r i c A c i d 8 8 b ) 1 3 1 I - L a u r i c A c i d 102 c ) N a I - 1 3 1 (6% HSA) I l l i x TABLE OF CONTENTS ( C o n t d . ) P a g e d) C o m p a r a t i v e M y o c a r d i a l U p t a k e o f 1 3 1 i _ c a p r i c A c i d , .1 3 1 1 - L a u r i c A c i d , and N a I - 1 3 1 (6% HSA) 119 5 . T o x i c i t y S t u d i e s 124 a ) 1 2 - B r o m o l a u r i c A c i d 124 b ) 1 0 - B r o m o c a p r i c A c i d . . . 129 6 . E x c r e t i o n S t u d i e s 132 a ) 1 3 1 I - C a p r i c A c i d 134 ( i ) C o m p a r t m e n t a l A n a l y s i s . . . . . . . 134 ( i i ) U r i n a r y A n a l y s i s 137 b ) 1 3 1 I - L a u r i c A c i d 139 ( i ) C o m p a r t m e n t a l A n a l y s i s 139 ( i i ) U r i n a r y A n a l y s i s 141 c ) N a I - 1 3 1 (6% HSA) 142 ( i ) C o m p a r t m e n t a l A n a l y s i s 142 d ) C a l c u l a t i o n o f t h e R e n a l H a l f - l i f e 1 4 6 7 . T h e R a d i o n u c l i d e S c a n s U s i n g t h e S e a r l e Gamma C a m e r a 147 a) 1 3 1 I - C a p r i c A c i d 147 b) 1 3 1 I - L a u r i c A c i d 149 c ) N a I - 1 3 1 (6% HSA) 149 d ) T h a l l i u m - 2 0 1 152 e ) C o m p a r i s o n o f R a d i o n u c l i d e S c a n s 152 8 . D o s i m e t r y 155 123 a ) T h e o r e t i c a l A b s o r b e d Dose f r o m I - C a p r i c o r ' " i - L a u r i c A c i d s 157 ( i ) W h o l e B o d y D o s i m e t r y . . . . . . . . 157 ( 1 ) 1 3 1 I - C a p r i c A c i d 159 ( 2 ) 1 3 1 I - L a u r i c A c i d 160 X TABLE OF CONTENTS ( C o n t d . ) P a g e ( i i ) The C u m u l a t e d A c t i v i t y 162 ( 1 ) 1 2 3 I - C a p r i c A c i d 1 6 2 ( 2 ) 1 2 3 I - L a u r i c A c i d 163 ( i i i ) T h e Mean Dose 1 6 4 (1) ^ I - C a p r i c A c i d 164 ( 2 ) ^ I - L a u r i c A c i d 165 V . SUMMARY AND CONCLUSIONS 170 V I . BIBLIOGRAPHY 174 x i L I S T OF TABLES T a b l e P a g e I R a d i o a c t i v i t y I n j e c t e d f o r M y o c a r d i a l S c a n s . . . . . . . . . . . 72 I I M e l t i n g P o i n t s o f B r o m i n a t e d F a t t y A c i d A n a l o g s . . . . 73 I I I Rf V a l u e s o f F a t t y A c i d s a n d T h e i r A n a l o g s U s i n g V a r i o u s D e t e c t i n g R e a g e n t s 74 IV R f V a l u e s o f F a t t y A c i d s and T h e i r A n a l o g s U s i n g V a r i o u s D e v e l o p i n g S o l v e n t s 75 V T h e E f f e c t o f T i m e on t h e R a d i o c h e m i c a l Y i e l d s o f R a d i o i o d i n a t e d F a t t y A c i d s (No R e f l u x i n g ) 77 VI The E f f e c t o f V a r i a b l e V o l u m e s o f N a I - 1 3 1 on t h e R a d i o c h e m i c a l - Y i e l d s o f R a d i o i o d i n a t e d F a t t y A c i d s . 80 V I I T o t a l U p t a k e o f ° I - C a p r i c A c i d by t h e S p l e e n , S t o m a c h , L a r g e and S m a l l I n t e s t i n e s , M u s c l e , and Bone o f Mi ce . . . . 89 131 V I I I R e l a t i v e O r g a n U p t a k e o f I - C a p r i c A c i d i n M i c e . . 96 131 IX O r g a n / B l o o d D i s t r i b u t i o n o f I - C a p r i c A c i d i n M i c e . 99 1 31 X T o t a l U p t a k e o f I - L a u r i c A c i d by t h e S p l e e n , S t o m a c h , I n t e s t i n e s , M u s c l e , and Bone o f M i c e . . . . 1 0 3 131 XI R e l a t i v e O r g a n U p t a k e o f I - L a u r i c A c i d i n M i c e . . 107 131 X I I O r g a n / B l o o d D i s t r i b u t i o n o f I - L a u r i c A c i d i n M i c e . . v . 109 X I I I T o t a l U p t a k e o f N a I - 1 3 1 (6% HSA) by t h e S p l e e n , S t o m a c h , I n t e s t i n e s , M u s c l e , a n d Bone o f M i c e . . . . 112 XIV R e l a t i v e O r g a n U p t a k e o f N a I - 1 3 1 (6% HSA) i n M i c e . . 115 XV O r g a n / B l o o d D i s t r i b u t i o n o f N a I - 1 3 1 (6% HSA) i n M i c e . 117 XVI D e t e r m i n a t i o n o f t h e L D j - n f o r N a - B r o m o l a u r a t e i n 10% Human Serum A l b u m i n 5 126 X V I I D e t e r m i n a t i o n o f t h e I n t r a v e n o u s L D ^ Q f o r 1 0 - B r o m o c a p r i c A c i d S o l u t i o n i n M i c e 130 X V I I I The E f f e c t o f S h e l f L e v e l s a n d A x i a l D i r e c t i o n on C o u n t R a t e s U s i n g t h e T u b o r 1 3 3 x i i L I S T OF TABLES ( C o n t d . ) T a b l e P a g e 131 X I X E x c r e t i o n o f I - C a p r i c A c i d i n U r i n e a n d F e c e s o f M i c e . • 1 3 8 131 XX E x c r e t i o n o f I - L a u r i c A c i d i n U r i n e a n d F e c e s o f M i c e 141 1 31 XXI C o m p a r i s i o n o f H a l f - l i v e s f o r I - C a p r i c A c i d , I S l l - L a u r i c A c i d , a n d N a I - 1 3 1 (6% HSA) 143 X X I I C o m p a r i s o n o f t h e E f f e c t i v e H a l f - L i v e s a n d t h e P e r c e n t a g e s E l i m i n a t e d by t h e T h r e e C o m p o n e n t s o f t h e E l i m i n a t i o n C u r v e s 1 4 3 X X I I I S, A b s o r b e d Dose U n i t C u m u l a t e d A c t i v i t y 162 XXIV The Mean A b s o r b e d Dose t o t h e W h o l e B o d y , K i d n e y s , L i v e r , a n d M u s c l e U s i n g 1 2 3 i _ c a p r i c a n d ' 2 3 i _ i _ a u r i c A c i d s 166 XXV A b s o r b e d Dose F r a c t i o n s f o r t h e H e a r t . . . . . . . . 1 6 8 x i i i L I S T OF FIGURES F i g u r e s P a g e 1 . S c h e m a t i c O u t l i n e o f t h e B e t a O x i d a t i o n C y c l e o f F a t t y A c i d s w i t h an Even Number o f C a r b o n Atoms . . 47 2 . R a d i o c h e m i c a l Y i e l d s o f R a d i o i o d i n a t e d F a t t y A c i d s by B r o m i n e R e p l a c e m e n t 78 3 . S t a b i l i t y o f R a d i o i o d i n a t e d F a t t y A c i d s i n 6% Human Serum A l b u m i n 81 4 . T o t a l M y o c a r d i a l U p t a k e o f 2 - I o d o t e t r a d e c a n o i c A c i d , 1 0 - I o d o d e c a n o i c A c i d , and 1 2 - I o d o l a u r i c A c i d i n M i c e . 8 3 5 . R e l a t i v e M y o c a r d i a l U p t a k e o f 2 - I o d o t e t r a d e c a n o i c A c i d , 1 0 - I o d o d e c a n o i c A c i d , and 1 2 - I o d o l a u r i c A c i d i n M i c e ' 8 5 6 . M y o c a r d i a l / B l o o d D i s t r i b u t i o n o f 2 - I o d o t e t r a d e c a n o i c A c i d , 1 0 - I o d o d e c a n o i c A c i d , a n d 1 2 - I o d o l a u r i c A c i d i n M i c e 86 7 . T o t a l O r g a n U p t a k e o f 1 0 - I o d o c a p r i c A c i d by L i v e r , H e a r t , L u n g , K i d n e y s , and B l o o d i n M i c e 90 8 . R e l a t i v e U p t a k e o f 1 0 - I o d o c a p r i c A c i d by L i v e r , H e a r t , L u n g , K i d n e y s , and B l o o d i n M i c e 97 9 . O r g a n / B l o o d D i s t r i b u t i o n o f 1 0 - I o d o c a p r i c A c i d by L i v e r , H e a r t , L u n g , and K i d n e y s i n M i c e 100 1 0 . T o t a l O r g a n U p t a k e o f 1 2 - I o d o l a u r i c A c i d by L i v e r , H e a r t , L u n g , K i d n e y s , and B l o o d i n M i c e . . . 104 1 1 . R e l a t i v e . . U p t a k e o f 1 2 - I o d o l a u r i c A c i d by L i v e r , H e a r t , L u n g , K i d n e y s , a n d B l o o d i n M i c e 108 1 2 . O r g a n / B l o o d D i s t r i b u t i o n o f 1 2 - I o d o l a u r i c A c i d by L i v e r , H e a r t , L u n g , and K i d n e y s i n M i c e 110 1 3 . T o t a l O r g a n U p t a k e o f N a I - 1 3 1 (HSA) by L i v e r , H e a r t , L u n g , K i d n e y s , a n d B l o o d i n M i c e 113 1 4 . R e l a t i v e U p t a k e o f N a I - 1 3 1 (HSA) by L i v e r , H e a r t , L u n g , K i d n e y s , and B l o o d i n M i c e 116 1 5 . O r g a n / B l o o d D i s t r i b u t i o n o f N a I - 1 3 1 (HSA) by L i v e r , H e a r t , L u n g , a n d K i d n e y s i n M i c e 118 x i v L I S T OF FIGURES ( C o n t d . ) FIGURES P a g e 1 6 . T o t a l M y o c a r d i a l U p t a k e o f 1 0 - I o d o d e c a n o i c A c i d , 1 2 - I o d o l a u r i c A c i d , and N a I - 1 3 1 (HSA) i n M i c e . . 120 17 . R e l a t i v e M y o c a r d i a l U p t a k e o f 1 0 - I o d o d e c a n o i c A c i d , 1 2 - I o d o l a u r i c A c i d , and N a I - 1 3 1 (HSA) i n M i c e 121 1 8 . M y o c a r d i a l / B l o o d D i s t r i b u t i o n o f 1 0 - I o d o d e c a n o i c A c i d , 1 2 - I o d o l a u r i c A c i d . , and N a I - 1 3 1 (HSA) i n M i c e . . 1 2 3 1 9 . W h o l e - b o d y E x c r e t i o n o f 1 0 - I o d o d e c a n o i c A c i d A f t e r I n t r a v e n o u s I n j e c t i o n i n M i c e 136 2 0 . W h o l e - B o d y E x c r e t i o n o f 1 2 - I o d o l a u r i c A c i d A f t e r I n t r a v e n o u s I n j e c t i o n i n M i c e 140 2 1 . W h o l e - B o d y E x c r e t i o n o f N a I - 1 3 1 (HSA) A f t e r I n t r a v e n o u s I n j e c t i o n i n M i c e 1 4 4 1 31 2 2 . S e r i a l S c a n s o f I - C a p r i c A c i d ( A n t e r i o r P r o j e c t i o n i n R a b b i t ) 148 131 2 3 . S e r i a l S c a n s o f I - L a u r i c A c i d ( A n t e r i o r P r o j e c t i o n i n R a b b i t ) . . . 150 2 4 . S e r i a l S c a n s o f N a I - 1 3 1 (6% HSA) ( A n t e r i o r P r o j e c t i o n i n R a b b i t ) 151 2 5 . T h a l l i u m - 2 0 1 S c a n i n R a b b i t ( A n t e r i o r P r o j e c t i o n i n R a b b i t a t 15 m i n u t e s ) 153 2 6 . D e c a y Scheme o f 1 2 3 I o d i n e 158 XV TO MY PARENTS x v i ACKNOWLEDGEMENT I w o u l d l i k e t o a c k n o w l e d g e t h e a s s i s t a n c e f r o m D r . D . M . L y s t e r t h r o u g h o u t t h i s s t u d y . I w i s h a l s o t o t h a n k L a u r a F o r d , Y . K . Tarn, H e l e n B u r t , R. V e n k a t a m a r a m e n , P a t T o y , a n d R. Chu f o r t h e i r e n c o u r a g e m e n t and s u p p o r t . S p e c i a l t h a n k s t o R. B u r t o n f o r h i s a s s i s t a n c e i n t h e c o m p u t e r a n a l y s i s . I n a d d i t i o n , I w o u l d l i k e t o t h a n k t h e members o f my c o m m i t t e e f o r t h e i r comments and s u g g e s t i o n s . The f i n a n c i a l a s s i s t a n c e f r o m t h e S t a n l e y D r u g - N o v o G r o u p S c h o l a r s h i p a n d t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a F e l l o w s h i p i s g r a t e f u l l y a c k n o w l e d g e d . I INTRODUCTION 1 The w o r d i n f a r c t i o n comes f r o m t h e L a t i n t e r m " i n f a r c i r e " , w h i c h means t o s t u f f i n ( W a r t m a n , 1 9 6 3 ) . I t h a s been u s e d i n v a r i o u s c o n t e x t s a n d , i n t h e 1 9 t h c e n t u r y , was u s e d t o d e s c r i b e a m o r b i d c o n d i t i o n o f t h e t i s s u e s r e s u l t i n g f r o m o b s t r u c t i o n o f t h e c i r c u l a t i o n , a s by e m b o l u s o r t h r o m b u s ( W a r t m a n , 1 9 6 3 ) . A t t h e p r e s e n t t i m e , an a r e a o f c e l l d e a t h s e c o n d a r y t o i s c h e m i a w o u l d be t e r m e d a m y o c a r d i a l i n f a r c t i o n . I s c h e m i a o c c u r s when t h e a r t e r i a l s u p p l y becomes i n s u f f i -c i e n t t o a l l o w n o r m a l d e l i v e r y o f e x o g e n o u s s u b s t r a t e s a n d r e m o v a l o f c e l l u l a r m e t a b o l i t e s ( J e n n i n g s , 1 9 7 0 ; J e n n i n g s e t a l . , 1 9 7 5 ) . C o n s e q u e n t l y , i n t r a - c e l l u l a r r e s p i r a t i o n s w i t c h e s f r o m a e r o b i c o x i d a t i o n t o a n e r o b i c g l y c o l y s i s a n d g l y c o g e n o l y s i s . I n c i d e n c e o f A c u t e M y o c a r d i a l I n f a r c t i o n s D i s e a s e s o f t h e h e a r t a r e t h e m a i n c a u s e o f d e a t h s i n B r i t i s h C o l u m b i a ( M a c D o n a l d , 1 9 7 6 ) . A c u t e m y o c a r d i a l i n f a r c t i o n (AMI) h e a d s t h e l i s t o f h e a r t d i s e a s e s a n d r e s u l t i n h i g h m o r b i d i t y a n d m o r t a l i t y . Of t h e t o t a l d e a t h s r e c o r d e d i n B r i t i s h C o l u m b i a i n 1 9 7 4 , AMI was t h e c a u s a l f a c t o r i n 19% ( M a c D o n a l d , 1 9 7 6 ) . I t i s e s t i m a t e d t h a t 25% o f AMI p a t i e n t s d i e w i t h i n t h e f i r s t t h r e e h o u r s o f t h e f i r s t a t t a c k a n d an a d d i t i o n a l 10% d i e w i t h i n t h e f i r s t week ( S i 1 b e r a n d ' K a t z , 1975) I n v i e w o f t h i s h i g h m o r t a l i t y r a t e , i t i s c r u c i a l t o d i a g n o s e t h e m y o c a r d i a l damage w i t h i n a f e w h o u r s o f t h e i n f a r c t , a s t h e c l i n i c a l p r o g r e s s o f t h e p a t i e n t d e p e n d s d i r e c t l y on t h e q u a n t i t y o f r e s i d u a l , v i a b l e m y o c a r d i a l c e l l s . E a r l y e s t i m a t i o n o f i n f a r c t s i z e c o u l d t h e r e f o r e h a v e i m p o r t a n t i m p l i c a t i o n s r e g a r d i n g t h e p r o g n o s i s , t h e s e l e c t i o n o f t r e a t m e n t r e g i m e n t , t h e s c r e e n i n g o f p a t i e n t s f o r s u r g i c a l r e v a s c u l a r i z a t i o n , as w e l l as e v a l u a t i n g p h y s i o l o g i c 2 a n d p h a r m a c o l o g i c t h e r a p y f o r r e d u c i n g i n f a r c t s i z e ( H a r p e r e t a l . , 1 9 7 1 ) . By l i m i t i n g t i s s u e damage f o l l o w i n g c o r o n a r y o c c l u s i o n , i t may be p o s s i b l e t o p r e v e n t c o m p l i c a t i o n s s u c h a s pump f a i l u r e a n d c a r d i o g e n i c s h o c k . The I m p o r t a n c e o f E a r l y D i a g n o s i s o f AMI I n e x p e r i m e n t a l a n i m a l s t u d i e s , m y o c a r d i a l t i s s u e s s u p p l i e d by an o c c l u d e d v e s s e l d i d n o t show an e s s e n t i a l l y homogeneous a r e a o f n e c r o s i s ( B r a u n w a l d , 1 9 7 6 ) . I n 1 9 7 5 , Cox e t a l . i d e n t i f i e d t h r e e d i f f e r e n t c o n c e n t r i c z o n e s o f m y o c a r d i a l i n j u r y a f t e r c o r o n a r y l i g a t i o n i n d o g s . T h e s e z o n e s i n c l u d e d a) a c e n t r a l a r e a o f n e c r o s i s , b) an i n t e r m e d i a t e z o n e o f i s c h e m i a , a n d c ) a z o n e o f n o r m a l t i s s u e . I t a p p e a r e d t h a t t h i s " i n t e r m e d i a t e z o n e " was i s c h e m i c b u t s t i l l v i a b l e . H o w e v e r , i t was g r a d u a l l y b e i n g i n f i l t r a t e d by t h e c e n t r a l n e c r o t i c z o n e . The f a t e o f t h e i n t e r m e d i a t e z o n e d e p e n d e d on t h e m y o c a r d i a l o x y g e n s u p p l y - d e m a n d r e l a t i o n s h i p , t h e a v a i l a b i l i t y o f n u t r i e n t s , as w e l l as t h e i n f l a m m a t o r y r e a c t i o n i t s e l f ( W e i s s e t a l . , 1 9 7 6 ; Cox e t a l . , 1 9 7 5 ) . I n t e r v e n t i o n s w h i c h m o d i f y t h e s e f a c t o r s may t h e r e f o r e l i m i t f u r t h e r i s c h e m i c i n j u r y , and c o n s e q u e n t l y a f f e c t t h e u l t i m a t e s i z e o f t h e i n f a r c t ( H a r r i s o n e t a l . , 1 9 7 6 ; R o s s a n d F r a n k l i n , 1 9 7 6 ) . D i a g n o s i s o f A c u t e M y o c a r d i a l I n f a r c t i o n s P h y s i c a l symptoms a r e h i g h l y v a r i a b l e i n AMI a n d t h e d i a g n o s i s i s commonly b a s e d on 3 p r i n c i p l e s : t h e h i s t o r y , t h e e l e c t r o c a r d i o g r a m ( E C G ) , a n d t h e s e r u m e n z y m e s ( F o w l e r , 1 9 7 6 ) . 1 . Hi s t o r y : I f t h e p a t i e n t i s c o n s c i o u s and l u c i d , he i s a b l e t o s u p p l y 3 p e r t i n e n t d e t a i l s r e g a r d i n g t h e o n s e t o f p a i n . H o w e v e r , t h i s i s n o t p o s s i b l e i f he h a s s u f f e r e d a s i l e n t i n f a r c t o r i f he i s c o m a t o s e . 2 . E l e c t r o c a r d i o g r a m s : E l e c t r o c a r d i o g r a m f i n d i n g s c a n be d i a g n o s t i c i f s e r i a l c h a n g e s a r e o b s e r v e d . ECG r e s u l t s a r e o f v a l u e when t h e p a t i e n t i s v e r y i l l o r i f t h e h i s t o r y i s a t y p i c a l o f A M I . I n t h e a b s e n c e o f s e r i a l c h a n g e s , t h e d i a g n o s i s may be e q u i v o c a l as p a t h o l o g i c : - Q wave c h a n g e s may be a s s o c i a t e d w i t h d i s o r d e r s o t h e r t h a n AMI ( F o w l e r , 1 9 7 6 ) . A l t h o u g h a c h a n g e i n ECG may be o b s e r v e d , i t i s n o t d i a g n o s t i c i n 4 0 - 5 0 % o f t h e p a t i e n t s ( F o w l e r , 1 9 7 6 ) . The t i m i n g o f e l e c t r o c a r d i o g r a m s i s v e r y i m p o r t a n t as e a r l y m y o c a r d i a l i n f a r c t i o n f e a t u r e s may d i f f e r f r o m t h e l a t t e r p a t t e r n . I f a r e c o r d i s made e a r l y , 1 - 2 h o u r s a f t e r t h e o n s e t o f p a i n , t h e c h a r a c t e r i s t i c Q w a v e s a r e a b s e n t ( F o w l e r , 1 9 7 6 ) . T h e r e may be p r o m i n e n t T waves w i t h an e l e v a t i o n o f t h e S - T s e g m e n t i n d i c a t i n g t h e a r e a o f e l e c t r i c a l i n v o l v e m e n t . C h a n g e s i n t h e Q p a t t e r n s a r e u s u a l l y n o t o b s e r v e d u n t i l s e v e r a l h o u r s t o one d a y a f t e r t h e A M I . 3 . S e r u m E n z y m e s : T h e r e a r e many e n z y m e s w h i c h c a t a l y s e b i o c h e m i c a l r e a c t i o n s i n t h e h e a r t . The s e r u m l e v e l s o f v a r i o u s e n z y m e s may be i n c r e a s e d i n AMI as w e l l a s i n o t h e r d i s e a s e s . The r e s u l t s o f t h e enzyme t e s t , s h o u l d be i n t e g r a t e d w i t h t h e ECG f i n d i n g s a n d t h e p a t i e n t ' s h i s t o r y i n o r d e r t o a s s e s s t h e d e g r e e o f m y o c a r d i a l n e c r o s i s ( F o w l e r , 1 9 7 6 ; S i l b e r a n d K a t z , 1 9 7 5 ) . . : 7 h e m a g n i t u d e a n d . t h e d u r a t i o n , o f - e l e v a t i o n . o f t h e s e r u m enzymes a r e r o u g h l y p r o p o r t i o n a l t o t h e mass o f t h e i r r e v e r s i b l y i n j u r e d m y o c a r d i a l c e l l s a n d c o u l d be u s e d i n p r o g n o s i s (Rao a n d M u e l l e r , 1 9 7 6 ; S h e l l e t a l . , 1 9 7 6 ; S h e l l e t a l . , 1 9 7 3 ) . Enzymes u s e d i n t h e d i a g n o s i s 4 o f AMI i n c l u d e SGOT, L D H , a n d CPK. I t i s c u s t o m a r y t o a s s a y a t l e a s t two o f t h e e n z y m e s t o e x c l u d e n o n - c o r o n a r y c o n d i t i o n s . a) SGOT - - S e r u m g l u t a m i c o x a l o a c e t i c t r a n s a m i n a s e l e v e l s p e a k i n 2 4 - 4 8 h o u r s a f t e r A M I . T r u e p o s i t i v e v a l u e s a r e r e p o r t e d i n 9 7 - 9 8 % o f AMI ( F o w l e r , 1 9 7 6 ; S i l b e r a n d K a t z , , 1 9 7 5 ) . E l e v a t e d - - S G O T l e v e l s - a l o n e ' a r e n o t d i a g n o s t i c a s l e v e l s may be i n c r e a s e d i n l i v e r d i s e a s e , h e p a t i c c o n g e s t i o n , c o n g e s t i v e h e a r t f a i l u r e , s h o c k , a n d o t h e r s k e l e t a l m u s c l e d i s o r d e r s ( F o w l e r , 1 9 7 6 ; S i l b e r a n d K a t z , , 1 9 7 5 ) v I n a d d i t i o n ' ; ' S G O T ' v a l u e s m a y ; ' b e n o r m a l i n . p a t i e n t s w i t h s u b e n d o c a r d i a l i n f a r c t i o n s . b) LDH - - L a c t i c d e h y d r o g e n a s e i s f o u n d i n t h e s e r u m a s w e l l as i n o t h e r o r g a n s i n c l u d i n g t h e h e a r t , s k e l e t a l m u s c l e , l i v e r , k i d n e y , p a n c r e a s , s p l e e n , b r a i n a n d l u n g s . Due t o i t s w i d e d i s t r i b u t i o n . t h r o u g h o u t t h e b o d y , e l e v a t i o n i n LDH l e v e l s i s n o t s p e c i f i c f o r AMI a n d d i a g n o s t i c a c c u r a c y i s l e s s t h a n w i t h SGOT. The t r u e p o s i t i v e e l e v a t i o n s o f LDH h a v e b e e n r e p o r t e d i n 8 5 - 8 6 % o f i n f a r c t p a t i e n t s ( F o w l e r , 1 9 7 6 ) . LDH a c t i v i t y e x c e e d s n o r m a l l e v e l s w i t h i n 2 4 - 4 8 h o u r s , p e a k s i n 3 - 6 d a y s , a n d r e t u r n s t o n o r m a l by 8 - 1 4 d a y s . c ) CPK - - C r e a t i n e p h o s p h o k i n a s e i s more d i s t i n c t i v e f o r m y o c a r d i a l i n f a r c t i o n s a n d i s u s u a l l y a s e n s i t i v e i n d i c a t o r ( F o w l e r , 1 9 7 6 ) . S e r u m CPK a c t i v i t y t y p i c a l l y p e a k s i n 24 h o u r s a f t e r A M I . The h e i g h t a n d d u r a t i o n o f s e r i a l s e r u m CPK c h a n g e s c o r r e l a t e w e l l w i t h t h e s i z e o f t h e i n f a r c t a n d r e p r e s e n t s a p r o g n o s t i c g u i d e t o A M I . 5 MYOCARDIAL IMAGING The c o n v e n t i o n a l d i a g n o s t i c m e t h o d s s u c h as s e r u m e n z y m e s a n d ECG a r e r a t h e r l i m i t e d f o r t h e e a r l y d i a g n o s i s o f m y o c a r d i a l l e s i o n s . M y o c a r d i a l s c a n s , h o w e v e r , a r e a h i g h l y s e n s i t i v e a n d n o n - i n v a s i v e m e t h o d o f c o r r e l a t i n g t h e s i z e , s i t e , a n d e x t e n t o f n e c r o t i c i n j u r y . T h i s e a r l y d i a g n o s i s p e r m i t s c a r d i a c a s s i s t a n c e o r s u r g i c a l t r e a t m e n t t o be i n s t i t u t e d b e f o r e b l o o d f l o w c o n d i t i o n s d e t e r i o r a t e ( C o x e t a l . , 1 9 7 5 ) . M y o c a r d i a l i m a g i n g i s p a r t i c u l a r l y u s e f u l when t h e p a t i e n t has a s u g g e s t i v e h i s t o r y , b u t h a s e q u i v o c a l e l e c t r o c a r d i o g r a m s o r i s i n a coma ( Z a r e t e t a l . , 1 9 7 4 ) . E C G - s t u d i e s ; a r e + l i m i t e d i n t h a t i n t r a v e n t r i c u l a r d e f e c t s " c o u l d mask f i n d i n g s on an ECG. Enzyme s t u d i e s may n o t be u s e d i n t h e e a r l y c o u r s e o f AMI a s t h e l e v e l s may s t i l l be n o r m a l . I n a d d i t i o n , t h e p o s s i -b i l i t i e s o f p h y s i o l o g i c a l c o n d i t i o n s o t h e r t h a n AMI c a u s i n g t h e e l e v a t i o n o f s e r u m e n z y m e s m u s t f i r s t be e l i m i n a t e d . E v e n t h o u g h s e r i a l s e r u m enzyme l e v e l s may p r o v i d e e v i d e n c e o f A M I , t h e r e i s no i n d i c a t i o n o f t h e e x a c t l o c a t i o n o f t h e i n f a r c t . The u s e o f m y o c a r d i a l s c a n s h a s b e e n l i m i t e d due m a i n l y t o t h e h i g h c o s t . H o w e v e r , i n a r e c e n t s t u d y by G o r t e n ( 1 9 7 7 ) , t h e c o n v e n t i o n a l d i a g n o s t i c m e t h o d s w e r e f o u n d t o be o f c o m p a r a b l e c o s t s t o m y o c a r d i a l s c a n s . T h i s was a t t r i b u t e d t o t h e f a c t t h a t s e r i a l ECG and s e r i a l s e r u m enzyme s t u d i e s h a d t o be p e r f o r m e d t o p o s i t i v e l y i d e n t i f y A M I . A b n o r m a l f i r s t s c a n s h a d a s e n s i t i v i t y o f 8 6 % , c o n t r a s t e d t o 83% s e n s i t i v i t y f o r s e r i a l E C G , a n d 67% s e n s i t i v i t y f o r s e r u m e n z y m e s . I n v i e w o f t h e g r e a t e r s e n s i t i v i t y o f m y o c a r d i a l s c a n s a t a s h o r t e r i n t e r v a l a f t e r t h e a c u t e a t t a c k , m y o c a r d i a l s c a n s a r e v a l u a b l e d i a g n o s t i c a i d s . 6 T h e r e a r e two a p p r o a c h e s t o m y o c a r d i a l i m a g i n g . T h e s e a r e i m a g i n g a g e n t s w h i c h l o c a l i z e s e l e c t i v e l y i n n e c r o t i c t i s s u e s , and i m a g i n g a g e n t s w h i c h e s t i m a t e t h e r e g i o n a l c o r o n a r y f l o w i n i n t a c t , o x y g e n a t e d m y o c a r d i a l c e l l s . R a d i o p h a r m a c e u t i c a l s u s e d t o d e t e c t r e c e n t a c u t e m y o c a r d i a l i n f a r c t i o n s a r e s e l e c t i v e l y c o n c e n t r a t e d by damaged c e l l s a n d a r e i n d i c a t e d as ' h o t s p o t s ' on m y o c a r d i a l s c a n s . A l t h o u g h t h e e x a c t m e c h a n i s m o f l o c a l i z a t i o n may d i f f e r , t h e c o n c e n t r a t i o n o f t h e s e a g e n t s d e p e n d on some s t r u c t u r a l m o d i f i c a t i o n i n t h e n e c r o t i c c e l l s . R a d i o p h a r m a c e u t i c a l s u s e d f o r e s t i m a t i o n o f r e g i o n a l c o r o n a r y f l o w l o c a l i z e i n n o r m a l , f u n c t i o n a l m y o c a r d i a l c e l l s a n d show up a s a ' c o l d s p o t ' o r an, a r e a o f d e c r e a s e d u p t a k e i n a r e a s o f n e c r o s i s ( C o o p e r , 1 9 7 4 ) . A g e n t s o f t h i s g r o u p a r e u s u a l l y a n a l o g s o f i n t r a c e l l u l a r c a t i o n s , o f w h i c h p o t a s s i u m i s t h e p r o t o t y p e . B i o c h e m i c a l s u b s t r a t e s s u c h as g l u c o s e as w e l l as f a t t y a c i d s h a v e a l s o b e e n u s e d . R a d i o i o d i n a t e d F a t t y A c i d s L o n g - c h a i n f a t t y a c i d s a r e an i m p o r t a n t s o u r c e o f f u e l f o r t h e h e a r t . T e r m i n a l r a d i o i o d i n a t i o n o f t h e o m e g a - c a r b o n has b e e n s u c c e s s f u l l y c a r r i e d o u t by R o b i n s o n and L e e ( 1 9 7 5 ) . The r e s u l t a n t o m e g a - r a d i o i o d i n a t e d f a t t y a c i d h a s b e e n f o u n d t o b e h a v e s i m i l a r l y t o t h e p h y s i o l o g i c ' f a t t y a c i d m o l e c u l e . I o d i n e - 1 2 3 , a m o n o - e n e r g e t i c gamma e m i t t e r w i t h a 13.0 h o u r s h a l f - l i f e and a l m o s t i d e a l i m a g i n g p r o p e r t i e s h a s been u s e d t o l a b e l 1 6 - h e x a d e c e n o i c a c i d . H i g h q u a l i t y s c a n s w e r e o b t a i n e d w h i c h i n d i c a t e d t h e c l i n i c a l u s e f u l n e s s o f t h e s e f a t t y a c i d a n a l o g s ( R o b i n s o n a n d L e e , 1 9 7 5 ) . The r a p i d m y o c a r d i a l c l e a r a n c e o f t h e s e a g e n t s r e f l e c t s t h e f u n c t i o n a l 7 s t a t e o f t h e m y o c a r d i a l c e l l s a s w e l l a s a l l o w i n g r e p e a t e d i m a g i n g i f n e c e s s a r y ( P o e , 1 9 7 7 ) . The c y c l o t r o n f a c i l i t i e s a t TRIUMF p r o m i s e t o be a c o n v e n i e n t s o u r c e o f 1 - 1 2 3 . W i t h t h i s i n m i n d , we c a r r i e d o u t a s e a r c h f o r a l t e r -n a t i v e f a t t y a c i d s t o r a d i o i o d i n a t e . The p r e f e r r e d f a t t y a c i d i s a m o n o r u n s a t u r a t e d o d d - n u m b e r e d c a r b o n f a t t y a c i d o f medium t o l o n g c h a i n l e n g t h . S i n c e s y n t h e s i s o f o m e g a - b r o m i n a t e d f a t t y a c i d s i s p a r t i c u l a r l y l e n g t h y a n d o f l o w y i e l d s , i t was d e c i d e d t o o b t a i n o m e g a - b r o m i n a t e d f a t t y a c i d s f r o m c o m m e r c i a l l y a v a i l a b l e s o u r c e s . O b j e c t i v e s The p u r p o s e o f t h i s s t u d y was t o i n v e s t i g a t e t h e p o s s i b l e u s e o f 9 - i o d o t e t r a d e c a n o i c a c i d , 2 - i o d o t e t r a d e c a n o i c a c i d , 1 2 - i o d o l a u r i c a c i d , a n d 1 0 - i o d o c a p r i c a c i d a s m y o c a r d i a l i m a g i n g a g e n t s . I n v e s t i g a t i o n was t o i n c l u d e t h e i r d i s t r i b u t i o n , e x c r e t i o n , a n d t o x i c i t y i n m i c e as w e l l a s a s c a n i n a r a b b i t . A n s w e r s t o t h e f o l l o w i n g q u e s t i o n s w e r e s o u g h t . 1) Where do t h e r a d i o i o d i n a t e d f a t t y a c i d s l o c a l i z e ? 2 ) What a r e t h e t a r g e t / n o n - t a r g e t r a t i o s ? 3) What i s t h e m a j o r r o u t e o f e x c r e t i o n ? 4 ) How t o x i c a r e t h e s e compounds a n d t h e i r m e t a b o l i t e s ? 5) What i s t h e r a d i a t i o n e x p o s u r e t o t h e h e a r t , t o o t h e r o r g a n s , a s w e l l as t o t h e w h o l e a n i m a l ? 6 ) A r e t h e s e a g e n t s b e t t e r t h a n t h o s e c u r r e n t l y a v a i l a b l e f o r m y o c a r d i a l i m a g i n g ? 7a I I LITERATURE SURVEY 8 1 . M y o c a r d i a l E n e r g e t i c s I n o r d e r t o s u c c e s s f u l l y i m a g e any o r g a n , i t i s e s s e n t i a l t o u n d e r s t a n d t h e b a s i c p h y s i o l o g y o f t h e t i s s u e s i n v o l v e d ( H i l d n e r , 1 9 7 6 ) . The h e a r t , pumps b l o o d t h r o u g h o u t t h e b o d y , d e l i v e r i n g n u t r i e n t s , h o r m o n e s a n d o t h e r r e g u l a t o r y s u b s t a n c e s a n d r e m o v i n g m e t a b o l i c w a s t e s f r o m v a r i o u s r e g i o n s ( K a t z , 1 9 7 7 ) . The c a r d i a c m u s c l e c e l l s c o n t a i n a c o m p l e x c o n t r o l s y s t e m w h i c h i s c a p a b l e o f m o d u l a t i n g t h e p u m p i n g a c t i o n o f t h e h e a r t t o meet t h e c h a n g i n g demands o f t h e b o d y . The h e a r t t h e r e f o r e r e q u i r e s a d e q u a t e p e r f u s i o n a t a l l t i m e s t o s t e a d i l y g e n e r a t e m e t a b o l i c e n e r g y a t a h i g h r a t e ( S i l b e r . a n d K a t z , 1 9 7 5 ) . M e t a b o l i c e n e r g y , i n t h e f o r m o f a d e n o s i n e t r i p h o s p h a t e ( A T P ) c a n be g e n e r a t e d i n t h e h e a r t by" o x i d a t i v e p h o s p h o r y l a t i o n o r by a n a e r o b i c g l y c o l y s i s . I n t h e h e a l t h y h e a r t , a e r o b i c o x i d a t i o n p r e v a i l s b u t d u r i n g p e r i o d s o f i s c h e m i a , a n a e r o b i c g l y c o l y s i s o c c u r s . H o w e v e r , e n e r g y d e r i v e d f r o m a n a e r o b i c g l y c o l y s i s i s o n l y a b o u t 5% o f t h e e n e r g y g e n e r a t e d by o x i d a t i v e m e t a b o l i s m ( K a t z , 1 9 7 7 ) . T h i s l o w l e v e l o f e n e r g y i s i n a d e q u a t e f o r u s e f u l c a r d i a c w o r k . When i n s u f f i c i e n t e n e r g y i s g e n e r a t e d , m e t a b o l i c c h a n g e s o c c u r , b o t h on a m i c r o s c o p i c a n d a m a c r o s c o p i c s c a l e . T h e s e c h a n g e s i n f l u e n c e t h e d i s t r i b u t i o n o f t h e r a d i o p h a r m a c e u t i c a l s w i t h i n t h e h e a r t , t h u s a l l o w i n g v i s u a l d i f f e r e n t i a t i o n o f n o r m a l f r o m n e c r o t i c m y o c a r d i u m i n m y o c a r d i a l s c a n s . a ) A c u t e R e s p o n s e t o M y o c a r d i a l I s c h e m i a a n d I n f a r c t i o n I s c h e m i a i s t h e p r i m a r y e v e n t w h i c h l e a d s t o r e g i o n a l h y p o x i a a n d c e l l u l a r d a m a g e . C e l l u l a r damage becomes a g g r a v a t e d w i t h t i m e a n d r e s u l t s i n i n f a r c t i o n ( l i e f e r , 1 9 7 5 ) . No s t r u c t u r a l damage o c c u r s i f t h e 9 t h e p e r i o d o f i s c h e m i a i s l e s s t h a n 20 m i n u t e s . I f t h e d u r a t i o n o f i s c h e m i a i s f r o m 3 0 - 6 0 m i n u t e s , t h e c e l l s s u f f e r p a r t i a l l y r e v e r s i b l e i s c h e m i c damage w i t h t h e r e s u l t t h a t some c e l l s d i e . L o n g e r d u r a t i o n s o f i s c h e m i a r e s u l t s i n t h e d e a t h o f t h e i s c h e m i c c e l l s , a n d t h e s p r e a d o f damage t o t h e s u r v i v i n g c e l l s ( L e f e r , 1 9 7 5 ) . T h i s i s r e c o g n i z e d a s t h e b e g i n n i n g o f t h e i n f a r c t . I f i s c h e m i a p e r s i s t s , c e l l u l a r n e c r o s i s i s a c c o m p a n i e d by i n f l a m m a t i o n , a n d t h e m y o c a r d i a l i n f a r c t i o n s p r e a d s . C e l l i n j u r y i n m a r g i n a l l y i s c h e m i c a r e a s may o c c u r by 2 m e c h a n i s m s w h i c h i n v o l v e l o s s o f membrane i n t e g r i t y ( H o f f s t e i n e t a l . , 1 9 7 6 ) : ( i ) E a r l y e v e n t s l e a d t o l o s s o f s a r c o l e m m a l i n t e g r i t y w h i c h a l l o w s an u n c o n t r o l l e d e n t r y o f i o n s a n d m a c r o m o l e c u l e s i n t o t h e c e l l s a n d a c o n c o m i t a n t l o s s o f c e l l u l a r c y t o p l a s m i c c o n s t i t u e n t s , ( i i ) The e a r l y r e l e a s e o f i n t r a c e l l u l a r c o m p o n e n t s (may be l y s o s o m e s ) m a y . e x e r t g l y c o g e n o l y t i c a n d p r o t e o l y t i c e f f e c t s . I f t h e s a r c o l e m m a i s i n t a c t , i t may l e a d t o i n c r e a s e d o s m o t i c p r e s s u r e a n d c o n s e q u e n t i n t r a c e l l u l a r e d e m a . b) M o r p h o l o g i c a l F e a t u r e s o f A c u t e M y o c a r d i a l I n f a r c t i o n I s c h e m i a r e s u l t s i n e a r l y m a c r o s c o p i c c h a n g e s s u c h a s p a l l o r a n d c y a n o s i s , f o l l o w e d by s w e l l i n g i n t h e a r e a s u p p l i e d by t h e a f f e c t e d b l o o d v e s s e l ( S i l b e r and K a t z , 1 9 7 5 ) . D i s c o l o r a t i o n o c c u r s w i t h i n 3 6 - 4 8 h o u r s a n d t h e i n f a r c t e d t i s s u e s t u r n p u r p l i s h a s i f i t w e r e t h e s i t e o f h e m o r r h a g e ( S i l b e r a n d K a t z , 1 9 7 5 ) . The i n f a r c t e d r e g i o n t u r n s g r a y a f t e r t h e t h i r d d a y , a n d becomes s t r e a k e d w i t h y e l l o w . T h e s e s e r i a l c h a n g e s i n g r o s s a p p e a r a n c e r e s u l t f r o m c e l l u l a r i n f i l t r a t i o n by p o l y m o r p h o n u c l e a r l e u k o c y t e s . The d e g e n e r a t i o n o f m u s c l e f i b e r i s f o l l o w e d by r e m o v a l o f t h e n e c r o t i c c e l l s , w h i c h i s r e p l a c e d by g r a n u l a t i o n c e l l s a n d 10 s c a r t i s s u e ( S i l b e r a n d K a t z , 1 9 7 5 ) . The l e n g t h o f h e a l i n g d e p e n d s o n t h e s i z e a n d t h e e x t e n t o f t h e i n f a r c t i o n . W i t h i n 5 - 1 0 m i n u t e s , m i c r o s c o p i c e x a m i n a t i o n r e v e a l s c l u m p i n g o f n u c l e o p l a s m , and c y t o p l a s m i c d i s t o r t i o n w i t h v a c u o l e s ( H i l d n e r , 1 9 7 6 ) . F a t d r o p l e t s a r e d e p o s i t e d i n s i d e t h e c e l l m e m b r a n e . C a p i l l a r y d i l a t a t i o n , * c o n g e s t i o n , a n d e o s i n o p h i l i c c h a n g e s i n t h e m u s c l e f i b r e s o c c u r f r o m 1 2 - 1 8 h o u r s . A p p r o x i m a t e l y 24 h o u r s f o l l o w i n g t h e i n f a r c t i o n , l e u k o c y t i c i n f i l t r a t i o n t a k e s p p l a c e . The m u s c l e s a p p e a r f r a g m e n t e d a s c e l l u l a r i n f i l t r a t i o n b e g i n s a n d t h e n e c r o t i c t i s s u e i s r e m o v e d . Dead m u s c l e i s r e p l a c e d by g r a n u l a t i o n t i s s u e a n d f i b r o b l a s t s l a y down c o l l a g e n f r o m t h e s e c o n d week o n w a r d s ( S i l b e r a n d K a t z , 1 9 7 5 ) . A f t e r a m o n t h , t h e m o r p h o l o g i c age o f t h e i n f a r c t i s a s s e s s e d by t h e d e n s i t y a n d c e l l u l a r i t y o f t h e c o l l a g e n i n r e l a t i o n t o t h e mass o f t h e d e a d m u s c l e . c ) M i t o c h o n d r i a l C h a n g e s The o x i d a t i v e m e t a b o l i s m o f m y o c a r d i a l c e l l s o c c u r w i t h i n t h e m i t o c h o n d r i a . T h e s e s t r u c t u r e s a r e n u m e r o u s a n d a r e l o c a t e d w i t h i n . t h e c e l l s ( H i l d n e r , 1 9 7 6 ) . M y o c a r d i a l c e l l s w h i c h h a v e b e e n i s c h e m i c , w h e t h e r r e v e r s i b l y o r i r r e v e r s i b l y , a l l show s w o l l e n m i t o c h o n d r i a a n d r e l a x a t i o n o r s t r e t c h i n g o f t h e m y o f i b r i l s ( J e n n i n g s , 1 9 7 0 ) . I t a p p e a r s t h a t t h e i n c r e a s e d p e r m e a b i l i t y o f t h e m i t o c h o n d r i a l membrane i s a f a t a l e v e n t , p o s s i b l y p r o m o t i n g p r o t o n l e a k a g e a n d " o b i i v i a t i n g o x i d a t i v e p h o s p h o r y l a t i o n (Trump e t a l . , 1 9 7 6 ) . The a b i l i t y o f t h e c a r d i a c c e l l s t o f u n c t i o n a d e q u a t e l y i f t h e r e i s r e s t o r a t i o n o f b l o o d f l o w d e p e n d s o n t h e e x t e n t o f t h e damage t o t h e m i t o c h o n d r i a l c o m p o n e n t s a n d enzyme s y s t e m s ( T r u m p ^ e t a l . , 1976) I n i r r e v e r s i b l y damaged c e l l s , t h e m i t o c h o n d r i a i s e x t r e m e l y f r a g i l e , 11 a n d t h e r e , i s a l o s s o f m a t r i x . d e n s i t y a l o n g w i t h t h e a p p e a r a n c e - o f i n t r a m i t o c h o n d r i a l g r a n u l e s ( S o b e l , 1 9 7 4 ) . 2 . P o s i t i v e I n f a r c t - I m a g i n g A g e n t s R a d i o p h a r m a c e u t i c a l s w h i c h a r e i n c o r p o r a t e d i n t o m y o c a r d i a l i n f a r c t i o n s p r o v i d e a m e t h o d t o d e t e c t , t o l o c a l i z e , and t o q u a n t i t a t e t h e a r e a o f n e c r o t i c d a m a g e . T h e s e a g e n t s a r e a d m i n i s t e r e d i n t r a -v e n o u s l y , a n d a f t e r s u b s e q u e n t l o c a l i z a t i o n , t h e a c u t e l y damaged m y o c a r d i a l t i s s u e s c a n be e x t e r n a l l y v i s u a l i z e d a s a ' h o t s p o t ' o r a n a r e a o f i n c r e a s e d u p t a k e w i t h a gamma c a m e r a . P o s i t i v e i n f a r c t - i m a g i n g a g e n t s i n c l u d e G a l l i u m - 6 7 , ( K r a m e r e t a l . , 1 9 7 4 ; K r a m e r e t a l . , 1 9 7 3 ) ; M e r c u r y - 2 0 3 c o m p o u n d s , ( H a n s o n e t a l . , 1 9 7 7 ; R a m a n a t h a n e t a l . , 1 9 7 1 ; H u b n e r , 1 9 7 0 ; G o r t e n e t a l . , 1 9 6 6 ; C a r r e t a l . , 1 9 6 2 a ) , a n d T e c h n e t i u m - 9 9 m 99m c h e l a t e s , s u c h a s T c - p y r o p h o s p h a t e , ( K l e i n e t a l . , 1 9 7 7 ; H o l m a n e t a l . , 1 9 7 6 a ; B u j a e t a l . , 1 9 7 5 ; L o w e n t h a l e t a l . , 1 9 7 5 ; B o n t e e t a l . , 1 9 7 4 ) ; 99m T c - g l u c o h e p t o n a t e , ( H o l m a n e t a l . , 1 9 7 6 b ; Rossman e t a l . , 1 9 7 5 a ; QQm F i n k / B e n n e t t e t a l . , 1 9 7 4 ) ; a n d T c - t e t r a c y c l i n e , ( H o l m a n e t a l . , 1 9 7 5 ; Cook e t a l . , 1 9 7 4 ; D e w a n j e e a n d P r i n c e , 1 9 7 3 ) . A l t h o u g h t h e e x a c t m e c h a n i s m o f b i n d i n g may d i f f e r , e a c h r a d i o p h a r m a c e u t i c a l has d e f i n i t e a f f i n i t y f o r i n f a r c t e d t i s s u e s . I t i s g e n e r a l l y r e c o g n i z e d t h a t i n c o r p o r a t i o n o f i n f a r c t - a v i d r a d i o t r a c e r s a r e r e l a t e d t o t h e a l t e r a t i o n s i n t h e c e l l membranes a s s o c i a t e d w i t h i s c h e m i a . I t h a s b e e n h y p o t h e s i z e d t h a t t h e s e a g e n t s may b i n d e i t h e r 1) d i r e c t l y t o t h e s u l f h y d r y l g r o u p s o f p r o t e i n s 2) t o damaged p r o t e i n s , o r 3) t o i n t r a c e l l u l a r c a l c i u m i o n s ( P o e , 1 9 7 7 ) . I n o r d e r f o r t h e r a d i o t r a c e r s t o r e a c h a n d become f i x e d t o damaged c e l l s , t h e r e m u s t be 12 some r e s i d u a l b l o o d f l o w t o t h e i n f a r c t e d r e g i o n ( P i t t a n d S t r a u s s , 1 9 7 6 a ; Rossman e t a l . , 1 9 7 5 a ) . S u b s e q u e n t l y , t h e r a d i o p h a r m a c e u t i c a l m u s t be c l e a r e d f r o m t h e b l o o d a n d s u r r o u n d i n g o r g a n s b e f o r e a d e q u a t e i m a g e s c o u l d b e o b t a i n e d . T h i s o f t e n d e p e n d s o n t h e r e n a l f u n c t i o n o f t h e p a t i e n t ( P i t t a n d S t r a u s s , 1 9 7 6 b ) . a ) G a l l i u m - 6 7 As p r e v i o u s l y m e n t i o n e d , a c o n s e q u e n c e o f AMI i s t h e i n f l a m m a t o r y p r o c e s s , w h e r e b y t h e r e i s a c e l l u l a r i n f i l t r a t i o n b y p o l y m o r p h s a n d m o n o c y t e s t o t h e s i t e o f t h e i n j u r e d t i s s u e ( K r a m e r e t a l . , 1 9 7 4 ) . I t i s known t h a t G a l l i u m - 6 7 ( G a - 6 7 ) a c c u m u l a t e s i n i n f l a m m a t o r y a s w e l l a s n e o p l a s t i c c e l l s a n d t h e r e f o r e i t s r o l e a s an i n f a r c t - i m a g i n g a g e n t h a s b e e n i n v e s t i g a t e d ( K r a m e r e t a l , , 1 9 7 3 ; W i s e m a n . , e t a l . , 1 9 7 3 ; H i g a s i e t a l . , 1 9 7 2 ; E d w a r d s and H a y e s , 1 9 7 0 . ) U s i n g G a - c i t r a t e , m y o c a r d i a l s c a n s o b t a i n e d 2 4 - 4 8 h o u r s a f t e r c o r o n a r y l i g a t i o n o f d o g s showed t h a t t h e i n t e n s i t y o f t h e G a l l i u m - 6 7 u p t a k e c o r r e l a t e d w e l l w i t h t h e s e v e r i t y o f i s c h e m i c damage a n d t h e d e g r e e o f p o l y m o r p h o n u c l e a r l e u k o c y t e i n f i l t r a t i o n ( K r a m e r e t a l . , 1 9 7 4 ) . Good c o r r e l a t i o n s w e r e a l s o o b t a i n e d b e t w e e n h i s t o l o g i c s e c t i o n s a n d s e r u m CPK l e v e l s w i t h t h e G a - 6 7 c o n c e n t r a t i o n w i t h i n t h e i n f a r c t ( K r a m e r e t a l . , 1 9 7 3 ) . T h e r e w a s no G a l l i u m - 6 7 u p t a k e b y n o r m a l f u n c t i o n i n g m y o c a r d i a l c e l l s (Wiseman e t a l . , 1 9 7 3 ) . The d i s a d v a n t a g e o f G a - 6 7 l i e s m a i n l y i n t h e h i g h a c c u m u l a t i o n o f t h e r a d i o n u c l i d e b y t h e r e t i c u l o e n d o t h e l i a l e l e m e n t s o f t h e l i v e r a n d b o n e m a r r o w ( K r a m e r e t a l . , 1 9 7 4 ) . T h e r e f o r e , t h e i n f e r i o r b o r d e r s o f t h e h e a r t a r e o b s c u r e d i n s c a n s ( K r a m e r e t a l . , 1 9 7 4 ) . I n a d d i t i o n , t h e 13 u p t a k e o f t h e r a d i o n u c l i d e b y i n f a r c t e d m y o c a r d i u m a p p e a r e d i n c o n s i s t a n t , a s o n l y f i v e o u t o f e i g h t h e a r t s w i t h d o c u m e n t e d AMI s h o w e d p o s i t i v e G a l l i u m u p t a k e ( K r a m e r e t a l . , 1 9 7 4 ) . I t w o u l d a p p e a r t h a t t h e u p t a k e o f "^Ga by t h e i n f a r c t e d m y o c a r d i u m was a s e c o n d a r y p h e n o m e n a , b e i n g d e p e n d e n t o n t h e d e g r e e o f t h e i n f l a m m a t o r y r e s p o n s e . b) M e r c u r y - 2 0 3 Compounds The s u c c e s s f u l v i s u a l i z a t i o n o f p r i m a r y b r a i n t u m o r s w i t h 2 0 3 H g - N e o h y d r i n s u g g e s t e d i t s p o s s i b l e u s e a s a m y o c a r d i a l i n f a r c t -i m a g i n g a g e n t ( C a r r e t a l . , 1 9 6 2 a ; B l a u . a n d B e n d e r , 1 9 6 0 ) . I n i t i a l c a n i n e s t u d i e s by C a r r e t a l . i n 1962 showed p r o m i s i n g r e s u l t s and g o o d c o r r e l a t i o n b e t w e e n h i s t o l o g i c s a m p l e s , i n t a c t s c a n s , a n d s c a n s o f e x c i s e d h e a r t s . H o w e v e r , human t r i a l s w e r e d i s a p p o i n t i n g i n t h a t o n l y one o u t o f t h i r t e e n p a t i e n t s w i t h d o c u m e n t e d AMI had a p o s i t i v e s c a n ( C a r r e t a l . , 1 9 6 2 a ) . F u r t h e r s t u d i e s by G o r t e n e t a l . >(1965, 1 9 6 6 ) d e m o n s t r a t e d t h e 203 s e l e c t i v e u p t a k e o f H g - c h l o r m e r o d r i n b y damaged t i s s u e a s d e f i n i t e a r e a s o f i n c r e a s e d r a d i o a c t i v i t y i d e n t i f i a b l e o n m y o c a r d i a l s c a n s . T h e r e a p p e a r e d t o be g o o d a g r e e m e n t b e t w e e n ' h o t ' a r e a s a n d t h e s i t e o f g r o s s a n a t o m i c and h i s t o l o g i c e v i d e n c e o f i n f a r c t i o n ( G o r t e n e t a l . , 1 9 6 5 ) . O p t i m u m , r e s u l t s , h o w e v e r , w e r e n o t o b t a i n e d u n t i l 3 - 5 d a y s p o s t - ' • <" ••*• i n f a r c t i o n ( G o r t e n e t a l . , 1 9 6 5 ) . The s t u d i e s i n l i v i n g s u b j e c t s w e r e t h o u g h t t o be h i n d e r e d by t h e movement o f t h e h e a r t , t h e r a d i o -p h a r m a c e u t i c a l c o n c e n t r a t i o n i n t h e l u n g s , a n d t h e s c a t t e r c a u s e d b y t h e t h o r a c i c w a l l ( G o r t e n e t a l . , 1 9 6 6 ) . G o r t e n f e l t t h a t a c c u m u l a t i o n o f t h e r a d i o p h a r m a c e u t i c a l was p r o b a b l y due t o m e r c u r y b o u n d t o t h e 14 s u l f h y d r y l g r o u p o f t h e c e l l p r o t e i n s . I t m u s t be e m p h a s i z e d t h a t t h e p r e l i m i n a r y t r i a l s o f G o r t e n ' s u t i l i z e d v e r y l a r g e d o s e s w h i c h w o u l d n o t be p e r m i s s i b l e i n h u m a n s . O t h e r m e r c u r i a l c o m p o u n d s w e r e i n v e s t i g a t e d f o r i n f a r c t - i m a g i n g H g - 2 0 3 o r H g - 1 9 7 w e r e t a g g e d t o h y d r o x y - m e r c u r y d e r i v a t i v e s o f f l u o r e s c e i n ( M a l e k e t c a l . , 1 9 6 7 a ; M a l e k e t a l . , 1 9 6 7 b ) . T h e s e compounds w e r e a l s o s e l e c t i v e l y t a k e n up by t h e i n f a r c t . M a l e k f o u n d b r o m m e c u r a s c a n - 2 0 3 a n d m e c u r a s c a n - 2 0 3 t o be s u p e r i o r t o n e o h y d r i n f o r i m a g i n g ( M a l e k e t a l . , 1 9 6 7 b ) . I n j e c t i o n s w e r e made 24 h o u r s a f t e r c o r o n a r y l i g a t i o n a n d s c a n s p e r f o r m e d 2 4 , 4 8 a n d 72 h o u r s l a t e r . A l t h o u g h t h e r e was g o o d c o r r e l a t i o n o f AMI a n d t h e s c a n , t h e r e was a p p r e c i a b l e a c c u m u l a t i o n o f H g - 2 0 3 i n t h e l i v e r a n d g a l l b l a d d e r ( M a l e k e t a l . , 1 9 6 7 b ) . A d d i t i o n a l r e s e a r c h i n t h i s a r e a was c a r r i e d o u t b y R a m a n a t h a n 2 0 3 e t a l . ( 1 9 7 1 ) a n d S p a r e t a l . ( 1 9 7 0 ) w i t h H g - f l u o r e s c e i n d e r i v a t i v e s w h i c h s h o w e d p r o m i s i n g r e s u l t s i n a n i m a l m o d e l s . H o w e v e r , i n v i e w o f t h e s u b - o p t i m a l d e c a y c h a r a c t e r i s t i c s ' , t h e h i g h r a d i a t i o n d o s e t o t h e 203 l i v e r a n d k i d n e y , a n d t h e d i f f i c u l t y i n p r e p a r a t i o n o f p u r e H g - l a b e l e d 203 f l u o r e s c e i n ( D a v i s e t a l . , 1 9 7 6 ) , H g - d e r i v a t i v e s h a v e f a l l e n i n t o d i s u s e a s r a d i o p h a r m a c e u t i c a l s f o r m y o c a r d i a l i n f a r c t - i m a g i n g . c ) T e c h n e t i u m - 9 9 m C h e l a t e s ( i ) 9 9 m T c - t e t r a c y c l i n e T e t r a c y c l i n e h a s b e e n shown t o l o c a l i z e i n p a t h o l o g i c a l l y a l t e r e d t i s s u e s ( R a i l e t a l . , 1 9 5 7 ) . M a l e k e t a l . ( 1 9 6 3 ) s u g g e s t e d t h e p o s s i b l e c l i n i c a l u s e o f c o u p l i n g t e t r a c y c l i n e w i t h - - a . g a m m a - e m i t t i n g , r a d i o n u c l i d e f o r e x t e r n a l d e t e c t i o n o f m y o c a r d i a l i n f a r c t s . 15 ^ ' " T c - t e t r a c y c l i n e was p r e p a r e d a n d i n j e c t e d i n t o l i g a t e d c a n i n e h e a r t s . The a c c u m u l a t i o n o f t h e r a d i o p h a r m a c e u t i c a l i n t h e i n f a r c t e d t i s s u e s 99m was c h a r a c t e r i s t i c and r e p r o d u c i b l e . I t was f o u n d t h a t t h e T c -t e t r a c y c l i n e was b o u n d t o t h e m u s c l e p r o t e i n s w h i c h w e r e b i o l o g i c a l l y a l t e r e d b y i s c h e m i a . 99m A s t a b l e c o m p l e x o f T c - t e t r a c y c l i n e was s y n t h e s i z e d by Dewanjee e t . a l . i n 1973 u s i n g t h e s t a n n o u s c h l o r i d e r e d u c t i o n m e t h o d . 99m The s e l e c t i v e u p t a k e o f T c - t e t r a c y c l i n e b y d e a d c e l l s a s o p p o s e d t o v i a b l e c e l l s was shown b y D e w a n j e e a n d P r i n c e ( 1 9 7 3 ) i n t i s s u e c u l t u r e s o f human 1 i v e r . 99m Holman e t a l . ( 1 9 7 3 a ) e v a l u a t e d t h e u s e f u l n e s s o f T c -t e t r a c y c l i n e i n d o g s w h i c h had b e e n s u b j e c t e d t o c o r o n a r y l i g a t i o n . I n i t i a l l y , t h e r e was h i g h u p t a k e i n t h e l i v e r , t h e g a l l b l a d d e r , a n d t h e k i d n e y s . The o p t i m a l s c a n t i m e was f o u n d t o be 24 h o u r s , a t w h i c h t i m e t h e r e was m a x i m a l c o n c e n t r a t i o n s i n n e c r o t i c t i s s u e s . F u r t h e r e x p e r i m e n t a l s t u d i e s w e r e u n d e r t a k e n t o d e t e r m i n e t h e 99m a c c u r a c y o f T c - t e t r a c y c l i n e i n d e f i n i n g t h e e x t e n t o f i n f a r c t i o n s ( C o o k e t a l . , 1 9 7 4 ) . E x p e r i m e n t a l m y o c a r d i a l i n f a r c t s w e r e p r o d u c e d i n 99m d o g s a n d a f t e r a l a p s e o f 24 h o u r s , T c - t e t r a c y c l i n e was i n j e c t e d . E p i c a r d i a l e l e c t r o c a r d i o g r a p h y was o b t a i n e d a t 15 s i t e s a n d m o n o p h a s i c a c t i o n p o t e n t i a l s r e c o r d e d f r o m t h e same s i t e s . The a n i m a l s w e r e s a c r i f i c e d , t h e h e a r t s e x c i s e d , a n d b i o p s y s p e c i m e n s t a k e n a t t h e 15 s i t e s w h e r e e l e c t r o d e s had b e e n p l a c e d i n o r d e r t o d e t e r m i n e t h e 99m c o n c e n t r a t i o n o f T c - t e t r a c y c l i n e . Good c o r r e l a t i o n was f o u n d i n t h e s i z e and t h e l o c a t i o n o f t h e i n f a r c t i o n m e a s u r e d by MAP ( M o n o p h a s i c 16 A c t i o n P o t e n t i a l s ) , e p i c a r d i a l E C G s , and t h e y y n i T c - t e t r a c y c l i n e c o n c e n t r a t i o n s i n 17 o u t o f 18 a n i m a l s . A d d i t i o n a l e x p e r i m e n t s t o e l u c i d a t e t h e t i m e c o u r s e o f 99m T c - t e t r a c y c l i n e w e r e p e r f o r m e d by Holman a n d Zweiman ( 1 9 7 5 ) . H i s t o l o g i c s t u d y o f b i o p s y s a m p l e s showed t h e o p t i m a l i m a g i n g . t i m e t o be 4 8 h o u r s a f t e r t h e i n f a r c t i o n . I n u n c o m p l i c a t e d i n f a r c t s , i m a g i n g w o u l d n o t be d e f i n i t i v e i f t h e i n f a r c t s w e r e o l d e r t h a n 1 week (Wynne e t a l , 1 9 7 8 ) . A b n o r m a l s c a n s o b t a i n e d more t h a n o n e week a f t e r t h e o n s e t o f i n f a r c t i o n w o u l d s u g g e s t r e i n f a r c t i o n . I n v i e w o f t h e p r o m i s i n g p r e l i m i n a r y r e s u l t s o b t a i n e d w i t h 99m T c - t e t r a c y c l i n e i n t h e c a n i n e m o d e l , a p i l o t s t u d y was p e r f o r m e d t o a s s e s s t h e u t i l i t y o f d e t e c t i n g a n d s i z i n g AMI i n humans ( H o l m a n e t a l . , 1 9 7 4 ) . I n t h i s c l i n i c a l t r i a l , 14 a b n o r m a l s c a n s w e r e o b t a i n e d f r o m 14 p a t i e n t s who h a d s u s t a i n e d A M I . S c i n t i g r a p h i c and ECG l o c a l i -z a t i o n c o r r e l a t e d w e l l . The s i z e o f t h e i n f a r c t f r o m t h e s c a n s c o r r e l a t e d w e l l w i t h p e a k c r e a t i n e p h o s p h o k i n a s e l e v e l s . I n a d d i t i o n a l s t u d i e s , H o l m a n a n d Zweiman ( 1 9 7 5 ) d e m o n s t r a t e d 9 9 m t h a t : t h e g r e a t e s t c o n c e n t r a t i o n o f T c - t e t r a c y c l i n e was i n t h e p o r t i o n o f t h e h e a r t w h i c h h a d t h e h i g h e s t d e g r e e o f n e c r o s i s . T h e s e r e s u l t s w e r e s u b s t a n t i a t e d by Zweiman e t a t . ( 1 9 7 5 ) , who s h o w e d t h a t t h e " " ^ T c -t e t r a c y c l i n e o n l y c o n c e n t r a t e d i n a c u t e l y i n f a r c t e d t i s s u e s b u t n o t i n i s c h e m i c t i s s u e s . 99m A l t h o u g h T c - t e t r a c y c l i n e h a s b e e n shown t o c o n c e n t r a t e i n n e c r o t i c c e l l s , t h e c l i n i c a l u s e f u l n e s s i s i m p e d e d by t h e s l o w b l o o d 17 c l e a r a n c e o f t h e a n t i b i o t i c . A d e q u a t e s c a n s c a n n o t be o b t a i n e d u n t i l 24 h o u r s a f t e r i n j e c t i o n o f t h e r a d i o p h a r m a c e u t i c a l , by w h i c h t i m e t h e T c - 9 9 m h a s d e c a y e d t h r o u g h f o u r p h y s i c a l h a l f - l i v e s (Wynne e t a l . , 1 9 7 8 ) . 99m I n a d d i t i o n , t h e r e ; i s h i g h u p t a k e o f T c - t e t r a c y c l i n e i n t h e l i v e r w h i c h o b s c u r e s i n f a r c t s i n t h e a p e x o f t h e h e a r t . 99m ( i i ) T c - g l u c o h e p t o n a t e 99m - T c - s t a n n o u s g l u c o h e p t o n a t e h a s b e e n e v a l u a t e d a s a m y o c a r d i a l i m a g i n g a g e n t by v a r i o u s i n v e s t i g a t o r s ( H o l m a n e t a l . , 1 9 7 6 b ; Rossman e t a l . , 1 9 7 5 a ; F i n k / B e n n e t t e t a l . , 1 9 7 4 ) . I n i t i a l s t u d i e s by F i n k / B e n n e t t e t a l ( 1 9 7 4 ) w e r e e n c o u r a g i n g a n d s h o w e d a maximum r a t i o o f 20/: 1 o f i n f a r c t e d / n o r m a l m y o c a r d i u m a t 24 h o u r s . F u r t h e r s t u d i e s p e r f o r m e d i n d o g s s u b j e c t e d t o c o r o n a r y l i g a t i o n s h o w e d a r e a s o f i n c r e a s e d u p t a k e i n s c i n t i g r a m s done a s e a r l y as 6 h o u r s p o s t - i n f a r c t i o n , a l t h o u g h t h e b e s t r e s o l u t i o n was o b t a i n e d a t 24 h o u r s (Rossman e t a l . , 1 9 7 5 a ) . 99m L i m i t e d c l i n i c a l t r i a l s h a v e b e e n d o n e u s i n g T c - g l u c o h e p t o n a t e . I n p a t i e n t s w i t h c l i n i c a l l y d o c u m e n t e d A M I , Rossman e t a l . ( 1 9 7 5 b ) f o u n d t h a t 80% had p o s i t i v e s c a n s . S i z i n g o f t h e i n f a r c t s b a s e d on' t h e CPK l e v e l s d e m o n s t r a t e d a g e n e r a l a g r e e m e n t w i t h t h e s c i n t i g r a p h i c a p p e a r a n c e 99m 1 (Rossman e t a l . , 1 : 9 7 5 b ) . The r a p i d c l e a r a n c e o f T c - g l u c o h e p t o n a t e f r o m t h e b l o o d a l l o w e d i d e n t i f i c a t i o n o f p o s i t i v e s c a n s a s e a r l y a s 5 h o u r s a f t e r t h e o n s e t o f c h e s t p a i n ( R o s s m a n e t a l . , 1 9 7 5 b ) . H o w e v e r , t h e c o n t r a s t b e t w e e n i n f a r c t / n o r m a l b a c k g r o u n d a c t i v i t y was o f t e n t o o l o w f o r d e f i n i t i v e i d e n t i f i c a t i o n . 18 Additional clinical assessment of ""'Tc-glucoheptonate by Holman et al. (1976b) showed poor results. Only 3 out of 13 patients with clinical evidence of infarcts had true positive scans. Due to the variable results and the low quality scans obtained 99m using Tc-glucoheptonate, it is not generally accepted for use as an infarct-avid radiopharmaceutical. (i i i) 99mTc-pyrophosphate 99m Tc-pyrophosphate, a bone scanning agent, is currently the most satisfactory of the available positive infarct-imaging agents (Davis et al., 1976; Bonte et al,, 1975). Bonte et al. (1974) - first 99m postulated the use of Tc-pyrophosphate for myocardial infarct imaging. This was based on the observations of D'Agnostino and Chiga (1972) that in necrotic cells, the calcium seemed to be incorporated into a crystalline structure which was the hydroxyapatite. The studies of Shen and Jennings (1972) confirmed these observations. The initial results obtained by Bonte et al. (1974) were encouraging in that favorable imaging ratios of 10:1 were obtained for infarct/normal myocardium, with little uptake by blood, lung, or liver. However, accumulation of the tracer was not detectable until 12-24 hours after infarction. 99m Further studies with Tc-pyrophosphate clarified its infarct labeling ability (Buja et al., 1976). Electron microscope studies demonstrated consistent alterations in the mitochondria of infarcted areas. Electron dense spicules were observed which were thought to be apatite crystals. 19 D o c u m e n t e d c l i n i c a l t r i a l s o f W i l l e r s o n e t a l . ( 1 9 7 5 ) a n d P a r k e y e t a l . ( 1 9 7 4 ) showed p o s i t i v e s c a n s i n m o s t AMI p a t i e n t s a n d n e g a t i v e s c a n s i n t h e c o n t r o l p a t i e n t s . T h e r e a p p e a r e d t o be g o o d a g r e e m e n t i n t h e p a t i e n t s w i t h p o s i t i v e s c a n s a n d t h e ECG a n d enzyme e v i d e n c e o f A M I . The m a x i m a l m y o c a r d i a l i n f a r c t / n o r m a l r a t i o was 1 0 . 9 : 1 . H o w e v e r , t h e r e was n o t i c e a b l e u p t a k e by t h e . b o n e s . The r e s u l t s o f C o l e m a n e t a l . ( 1 9 7 6 ) w e r e a l s o e n c o u r a g i n g . A b n o r m a l s c a n s w e r e o b t a i n e d i n 23 o u t o f 25 p a t i e n t s w i t h d e f i n i t e c o n f i r m e d m y o c a r d i a l i n f a r c t s w h i l e t h e r e m a i n i n g 2 s c a n s w e r e e q u i v o c a l . P a r k e y e t a l . ( 1 9 7 6 ) e v a l u a t e d AMI i m a g i n g u s i n g b o t h 99m t h a l l i u m - 2 0 1 a s w e l l a s T c - p y r o p h o s p h a t e . I n 24 d o c u m e n t e d c a s e s 99m o f A M I , 22 h a d p o s i t i v e T c - p y r o p h o s p h a t e s c a n s . M o r e r e c e n t s t u d i e s b y P r a s q u i e r e t a l . ( 1 9 7 7 ) r e v e a l e d d i s c r e t e m y o c a r d i a l u p t a k e i n 2 5 / 2 6 p a t i e n t s w i t h t r a n s m u r a l i n f a r c t i o n s . B e r m a n e t a l . ( 1 9 7 7 ) d e m o n s t r a t e d 76 a b n o r m a l s c a n s o u t o f 81 p a t i e n t s w i t h a c u t e t r a n s m u r a l i n f a r c t s . The r e m a i n i n g 5 s c a n s w e r e e q u i v o c a l . 99m 99m T c - p y r o p h o s p h a t e i s t h e m o s t p r o m i s i n g o f t h e T c - c h e l a t e s f o r p o s i t i v e i n f a r c t - i m a g i n g . I m a g i n g c a n be s t a r t e d a b o u t 1 - 2 h o u r s a f t e r t h e i n j e c t i o n o f t h e r a d i o t r a c e r ( P o e , 1 9 7 7 ) . H o w e v e r , i n f a r c t s m u s t be a t l e a s t 12 h o u r s o l d t o be c o n s i s t e n t l y d e t e c t a b l e ( P o e , 1 9 7 7 ) , and t h e o p t i m u m t i m e f o r s c a n n i n g i s 2 4 - 4 8 h o u r s a f t e r t h e i n f a r c t i o n ( P a r k e y e t a l . , 1 9 7 6 ) . 99m U s i n g T c - p y r o p h o s p h a t e , t h e r e i s a b o u t a 6% f a l s e n e g a t i v e a n d a 17% f a l s e p o s i t i v e r a t e (Wynne e t a l . , 1 9 7 8 ) . Due t o t h e a v i d i t y 99m o f T c - p y r o p h o s p h a t e f o r b o n e , t h e r e i s s i g n i f i c a n t u p t a k e i n t h e 20 r i b s o r i n a n y i n j u r e d a r e a o f t h e s k e l e t a l s y s t e m . . S i m i l a r l y , b r e a s t t u m o r s , f u n c t i o n a l b r e a s t t i s s u e i n p r e - m e n o p a u s a l woman, a n d damage t o t h e c h e s t w a l l may l e a d t o p o s i t i v e s c a n s ( P a r k e y e t a l . , 1974-). More i m p o r t a n t a r e t h e p o s s i b l e c a r d i a c c a u s e s o f p o s i t i v e s c a n s o t h e r t h a n A M I . Two c a n c e r p a t i e n t s w i t h o u t e v i d e n c e o f AMI had l o c a l i z e d a r e a s o f u p t a k e i n t h e h e a r t ( S o i n s e t a l . , 1 9 7 5 ) . P o s i t i v e s c a n s h a v e a l s o b e e n r e p o r t e d i n p a t i e n t s w i t h u n s t a b l e a n g i n a , c a r d i a c c o n t u s i o n s , a n e u r y s m s , a n d c a r d i a c t u m o r s (Ahmad e t a l . , 1 9 7 6 ; P e r e z e t a l . , 1 9 7 6 ; Grames a n d J a n s e n , 1 9 7 3 ) . 99m C o n t r o v e r s y h a s a r i s e n o v e r t h e u p t a k e o f T c - p y r o p h o s p h a t e b y m y o c a r d i u m w h i c h i s n o t n e c r o t i c b u t m e r e l y i s c h e m i c . The p o s i t i v e s c a n s o b t a i n e d i n p a t i e n t s w i t h a n g i n a h a v e a d d e d t o t h i s c o n t r o v e r s y 99m a n d i t w o u l d a p p e a r t h a t T c - p y r o p h o s p h a t e may n o t be s p e c i f i c f o r n e c r o t i c c e l l s . 3 . N e g a t i v e I n f a r c t - I m a g i n g A g e n t s The s e c o n d c l a s s o f m y o c a r d i a l i m a g i n g a g e n t s i s d i s t r i b u t e d i n p r o p o r t i o n t o b l o o d f l o w a n d i s i n c o r p o r a t e d by i n t a c t , v i a b l e m y o c a r d i a l c e l l s . T h e s e a g e n t s show up a s a r e a s o f d e c r e a s e d u p t a k e o r ' c o l d s p o t s ' i n i s c h e m i c l e s i o n s . The d i s t r i b u t i o n o f t h e s e a g e n t s i s b a s e d o n t h e S a p i r s t e i n i n d i c a t o r f r a c t i o n a t i o n p r i n c i p l e , w h i c h p r e d i c t s t h a t a f t e r i n t r a v e n o u s a d m i n i s t r a t i o n , t h e u p t a k e o f r a d i o t r a c e r s b y t h e h e a r t i s e q u a l t o t h e f r a c t i o n o f t h e c a r d i a c o u t p u t p e r f u s i n g t h e h e a r t ( S a p i r s t e i n , 1 9 5 6 ) . T h e r e i s s u f f i c i e n t u p t a k e b y t h e m y o c a r d i u m t o p e r m i t e x t e r n a l i m a g i n g , s i n c e a p p r o x i m a t e l y 21 5 - 8 % o f t h e c a r d i a c o u t p u t . . s u p p l i e s t h e m y o c a r d i u m a t r e s t ( H o l m a n e t a l . , 1 9 7 3 b ) . a ) P o t a s s i u m P o t a s s i u m i s a p r i m a r y i n t r a c e l l u l a r c a t i o n w h o s e c o n c e n t r a t i o n i s d e p e n d e n t upon a c t i v e t r a n s p o r t ( P r o k o p e t a l . , 1 9 7 4 ) . A c t i v e t r a n s p o r t i s o x y g e n d e p e n d e n t a n d a n y p e r i o d s o f i s c h e m i a w i l l l e a d t o a d e c r e a s e i n t h e i n t r a c e l l u l a r p o t a s s i u m l e v e l s ( G e r l i n g s e t a l . , 1 9 6 9 ) . P o t a s s i u m i s a h i g h l y e x t r a c t a b l e , c e l l d e p e n d e n t , n o n - m e t a b o l i z a b l e t r a c e r a n d t h u s f u l f i l l s S a p i r s t e i n ' s c r i t e r i a f o r m e a s u r i n g m y o c a r d i a l b l o o d f l o w ( P o e , 1 9 7 5 ; S a p i r s t e i n , 1 9 5 6 ) . P o t a s s i u m i o n s a r e n o t s p e c i f i c f o r t h e m y o c a r d i u m , w h i c h o n l y r e c e i v e s 5 - 8 % o f t h e i n j e c t e d d o s e , w h i l e t h e r e m a i n i n g p o t a s s i u m i o n s a r e d i s t r i b u t e d t h r o u g h o u t t h e b o d y ( P o e , 1 9 7 5 ) . On a s i n g l e p a s s a g e t h r o u g h t h e h e a r t , h o w e v e r , o v e r 70% o f t h e a v a i l a b l e p o t a s s i u m f r o m t h e p l a s m a w i l l e n t e r t h e o x y g e n a t e d m y o c a r d i a l c e l l s ( P o e , 1 9 7 7 ; P o e , 1 9 7 2 ; L o v e e t a l . , 1 9 6 8 ) . L o v e e t a l . ( 1 9 5 4 ) w e r e t h e f i r s t t o s t u d y t h e m y o c a r d i a l a c c u m u l a t i o n o f p o t a s s i u m a n d i t s a n a l o g s . The r a t e o f r a d i o n u c l i d e u p t a k e by t h e m y o c a r d i u m was f o u n d t o be d e p e n d e n t o n t h e c o r o n a r y b l o o d f l o w a s w e l l a s t h e r a t e o f e x c h a n g e o f t h e e l e m e n t s b e t w e e n t h e c i r c u l a t o r y s y s t e m a n d t h e m y o c a r d i u m . 43 H u r l e y e t a l . ( 1 9 7 1 ) i n t r o d u c e d KC1 f o r c l i n i c a l m y o c a r d i a l i m a g i n g i n v i e w o f i t s f a v o r a b l e h a l f - l i f e a n d gamma p h o t o n s . K - 4 3 h a s a h a l f - l i f e o f 2 2 . 4 h o u r s a n d gamma p h o t o n s o f 373 a n d 619 K e V . S c a n s w e r e p e r f o r m e d on n o r m a l m e n , p a t i e n t s w i t h A M I , a s w e l l a s d o g s . 22 Normal s c a n s . d e m o n s t r a t e d w e l l v i s u a l i z e d v e n t r i c u l a r , m u s c l e a n d a c e n t r a l ' c o l d a r e a ' c o r r e s p o n d i n g t o t h e v e n t r i c u l a r c a v i t y . I n m y o c a r d i a l i n f a r c t s , a d d i t i o n a l c o l d s p o t s w e r e o b s e r v e d , w h i c h c o n f i r m e d t h a t K - 4 3 a p p e a r e d o n l y i n v i a b l e m y o c a r d i a l c e l l s . S u b s e q u e n t d i s t r i b u t i o n a n a l y s i s s h o w e d t h a t t h e m a x i m a l u p t a k e o f p o t a s s i u m b y t h e m y o c a r d i u m w a s between 5 - 2 0 m i n u t e s a f t e r i n t r a v e n o u s a d m i n i s t r a t i o n ( P o e , 1 9 7 2 ) . T h i s w o u l d be t h e o p t i m a l s c a n t i m e a s t h e p o t a s s i u m i s r a p i d l y c o n c e n t r a t e d by t h e m y o c a r d i u m and a l s o r a p i d l y c l e a r e d f r o m t h e b l o o d . G o r t e n ( 1 9 7 2 ) f u r t h e r e v a l u a t e d t h e c l i n i c a l u s e f u l n e s s o f 4 3 K - 4 3 f o r m y o c a r d i a l s c a n n i n g . A d m i n i s t r a t i o n o f . 9 - 1 . 5 c m C i o f KC1 i n 20 AMI p a t i e n t s was f o l l o w e d b y s c a n s . T h e r e w e r e d e f i n i t e s c a n a b n o r -m a l i t i e s f o u n d i n 19 o u t o f t h e 20 p a t i e n t s . Good a g r e e m e n t was f o u n d b e t w e e n ECG a n d enzyme c h a n g e s c o m p a r e d t o t h e i n f a r c t s i z e a n d l o c a t i o n o b t a i n e d f r o m m y o c a r d i a l s c a n s . The c o r r e l a t i o n o f m y o c a r d i a l K - 4 2 u p t a k e w i t h c o r o n a r y a r t e r i o g r a p h y was c o m p a r e d by B e n n e t t e t a l . ( 1 9 7 2 ) i n 12 p a t i e n t s . B e n n e t t e t a l . u t i l i z e d K - 4 2 i n v i e w o f t h e f a c t t h a t K - 4 3 was n o t r e a d i l y a v a i l a b l e . T h e r e was g o o d c o r r e l a t i o n i n p a t i e n t s w i t h l e s i o n s o f t h e a n t e r i o r d e s c e n d i n g a r t e r y u s i n g b o t h m e t h o d s . I t a p p e a r e d t h a t i t was p o s s i b l e t o e x t e r n a l l y d e t e c t a r e a s o f i s c h e m i c m y o c a r d i u m by d e c r e a s e d t r a c e r u p t a k e . The d e c r e a s e i n t h e u p t a k e o f K - 4 2 r e p r e s e n t e d i n a d e q u a t e c a p i l l a r y b l o o d f l o w a n d / o r r e p l a c e m e n t o f n o r m a l m y o c a r d i u m w i t h i n a c t i v e n e c r o t i c c e l l s . H o w e v e r , K - 4 2 was u n f a v o r a b l e due t o i t s l a r g e r a d i a t i o n d o s e t o t h e p a t i e n t . 23 Z a r e t e t a l . ( 1 9 7 3 a , 1 9 7 3 b ) a d m i n i s t e r e d ^ K C l i n t r a v e n o u s l y t o d e l i n e a t e a r e a s o f m y o c a r d i a l i n f a r c t i o n a s w e l l a s t r a n s i e n t l y i s c h e m i c t i s s u e s i n human s u b j e c t s . T h e s e s t u d i e s o f r e g i o n a l m y o c a r d i a l p e r f u s i o n w e r e a s s e s s e d a t r e s t , w i t h e x e r c i s e , a n d d u r i n g a n g i n a . W o r k i n g i n c o l l a b o r a t i o n w i t h Z a r e t e t a l . , S t r a u s s e t a l . ( 1 9 7 3 ) a l s o e v a l u a t e d K - 4 3 i n r e s t a n d e x e r c i s e m y o c a r d i a l p e r f u s i o n s t u d i e s . The r a t i o n a l e o f t h i s t e s t i n g was t h a t i n e x e r c i s e , t h e r e i s an i n c r e a s e i n c o r o n a r y b l o o d f l o w w h i c h i s m a r k e d i n r e g i o n s s u p p l i e d by n o r m a l c o r o n a r y a r t e r i e s b u t g r e a t l y r e d u c e d i n o c c l u d e d a r t e r i e s ( S t r a u s s e t a l . , 1 9 7 3 ) . E x e r c i s e a p p e a r e d t o m a x i m i z e t h e d i f f e r e n c e b e t w e e n n o r m a l a n d a b n o r m a l c o r o n a r y v a s c u l a r b e d s . T h e r e f o r e , b y c o m b i n i n g r e s t a n d e x e r c i s e s c a n s , t h e s i t e a n d t h e e x t e n t o f t r a n s i e n t m y o c a r d i a l i s c h e m i a c o u l d be e v a l u a t e d more a c c u r a t e l y . Good c o r r e l a t i o n s w e r e f o u n d b e t w e e n m y o c a r d i a l p e r f u s i o n u s i n g K - 4 3 a n d m i c r o s p h e r e s ( P r o k o p e t a l . , 1 9 7 4 ) . I n s u b s e q u e n t s t u d i e s , g a t e d c a r d i a c b l o o d p o o l s c a n n i n g was c o m b i n e d w i t h m y o c a r d i a l i m a g i n g u s i n g K - 4 3 . The a k i n e t i c a r e a s o f a g a t e d s c a n c o r r e s p o n d e d t o a d e c r e a s e i n K - 4 3 c o n c e n t r a t i o n ( R i g o e t a l . , 1 9 7 5 ) . The c o r r e l a t i o n o f t h e s i z e o f t h e a k i n e t i c z o n e a n d t h e d e c r e a s e i n u p t a k e o f t r a c e r K - 4 3 was u s e d t o a s s e s s t h e e x t e n t o f l e f t v e n t r i c u l a r w a l l i n v o l v e m e n t . H o w e v e r , K - 4 3 i o n s a l s o t e n d e d t o c o n c e n t r a t e i n t h e g a s t r i c m u s c o s a , t h u s o b s c u r i n g t h e i n f e r i o r w a l l o f t h e m y o c a r d i u m ( R i g o e t a l . , 1 9 7 5 ) . G o r t e n ( 1 9 7 7 ) p e r f o r m e d an e x t e n s i v e c l i n i c a l e v a l u a t i o n o f r a d i o p o t a s s i u m and i t s a n a l o g s . S e v e n t y o u t o f t h e e i g h t y p a t i e n t s w i t h m y o c a r d i a l i n f a r c t s d e m o n s t r a t e d a b n o r m a l K - 4 3 s c a n s , w h i c h 24 r e p r e s e n t e d a s e n s i t i v i t y o f 8 7 . 5 % . Of t h e 50 n o r m a l p a t i e n t s n o t s u f f e r i n g f r o m m y o c a r d i a l i n f a r c t s , 2 had a b n o r m a l s c a n s due t o c h e s t w a l l t r a u m a . K-,43 . c a n n o t d i f f e r e n t i a t e r e c e n t ' f r o m o l d i n f a r c t s . T h i s may be c l i n i c a l l y u s e f u l i n c a s e s o f i n c o n c l u s i v e h i s t o r i e s o r ECG r e g a r d i n g t h e r a p y o r r e h a b i l a ' t a t i b n . H o w e v e r , t h e i n a b i l i t y o f K - 4 3 t o be s i n g u l a r l y i n d i c a t i v e o f r e c e n t i n f a r c t s r u l e s o u t t h e p r e c i s i o n o f a b n o r m a l s c a n s . W h i l e t h e o v e r a l l r e s u l t s w i t h K - 4 3 h a v e b e e n p r o m i s i n g , t h e u s e o f t h e r a d i o n u c l i d e i s l i m i t e d by i t s r e l a t i v e l y h i g h c o s t a n d l a c k o f a v a i l a b i l i t y ; by b e t a - e m m i s s i o n r e s u l t i n g i n i n c r e a s e d r a d i a t i o n d o s e ; by t h e 373 gamma p h o t o p e a k , w h i c h i s n o t i d e a l f o r s c i n t i l l a t i o n c a m e r a s ; a s w e l l as by t h e 6 1 9 Ke.V p h o t o p e a k , w h i c h r e q u i r e s e x t r a s h i e l d i n g a n d c o n t r a s t e n h a n c e m e n t t o m i n i m i z e s c a t t e r , s e p t a l p e n e t r a t i o n , a n d p e n e t r a t i o n o f t h e c o l l i m a t o r ( H o l m a n , 1 9 7 4 ; P o e , 1 9 7 7 ) . The a n a l o g s o f p o t a s s i u m a r e m o n o - v a l e n t , a l k a l i n e m e t a l i o n s as R u b i d i u m (Rb) a n d C e s i u m . ( C s ) , w h i c h a r e c o n c e n t r a t e d a n d m a i n t a i n e d i n t h e c e l l by t h e same m e c h a n i s m as p o t a s s i u m . H o w e v e r , t h e e x t r a c t i o n e f f i c i e n c y a p p e a r s t o be i n v e r s e l y p r o p o r t i o n a l t o t h e s i z e o f t h e c r y s t a l r a d i u s o f t h e i o n ( P o e , 1 9 7 7 ) . b) R u b i d i u m R u b i d i u m h a s a c r y s t a l r a d i u s o f i n t e r m e d i a t e s i z e a n d i t s u p t a k e and c l e a r a n c e c l o s e l y r e s e m b l e s t h a t o f p o t a s s i u m ( P o e , 1 9 7 5 ; P a u l i n g , 1 9 6 9 ; , . L o v e e t a l . , 1 9 6 8 ) . I n a s e a r l y a s 1 9 5 4 , t h e i n i t i a l t i s s u e d i s t r i b u t i o n a n d r a t e o f r e d i s t r i b u t i o n o f K - 4 2 w e r e f o u n d t o be p a r a l l e l t o t h a t o f R b - 8 6 ( L o v e e t a l . , 1 9 5 4 ) . I n 1 9 5 8 , N o l t i n g e t a l . 25 m e a s u r e d t h e e f f e c t o f c o r o n a r y b l o o d f l o w o n R b - 8 6 e x t r a c t e d by t h e h e a r t . I t was f o u n d t h a t a s c o r o n a r y b l o o d f l o w d e c r e a s e d , t h e p e r c e n t a g e m y o c a r d i a l e x t r a c t i o n o f R b - 8 6 i n c r e a s e d . I t was t h o u g h t t h a t t h e R b - 8 6 d i f f u s e d i n t o a l a r g e m i s c i b l e p o o l . M y o c a r d i a l e x t r a c t i o n , m e a s u r e d by c o r o n a r y s i n u s c a t h e t e r i z a t i o n "was f o u n d t o be o n l y a b o u t 43% ( N o l t i n g e t a l . , 1 9 5 8 ) . H o w e v e r , l a t e r s t u d i e s o f m y o c a r d i a l e x t r a c t i o n o f R b - 8 6 s h o w e d v a l u e s o f 6 5 % , a n d t h e s e v a l u e s h a v e now b e e n a c c e p t e d a s t h e m y o c a r d i a l e x t r a c t i o n e f f i c i e n c y o f r u b i d i u m ( L o v e e t a l . , 1 9 6 8 ) . R u b i d i u m - 8 6 was f i r s t i n v e s t i g a t e d f o r m y o c a r d i a l i m a g i n g by C a r r e t a l . ( 1 9 6 2 ) . I t h a s a 1 8 . 7 days h a l f - l i f e a n d a p h o t o p e a k a t 1 .1 MeV. The p r i m a r y o r g a n s o f u p t a k e a p p e a r e d t o be t h e l i v e r a n d t h e h e a r t ( C a r r e t a l . , 1 9 6 2 b ) . H o w e v e r , i t r e q u i r e d s p e c i a l c o l l i m a t o r s t o r e d u c e i n t e r f e r e n c e f r o m o r g a n s a d j a c e n t t o t h e h e a r t , e s p e c i a l l y t h e l i v e r . I n a d d i t i o n , t h e w h o l e b o d y r a d i a t i o n d o s e was v e r y h i g h . I n 1 9 6 9 , L o v e , S m i t h and P u l l e y v e r i f i e d t h e s i m i l a r b i o l o g i c a l b e h a v i o r o f Rb a n d K i n t h e m y o c a r d i u m by m a p p i n g m y o c a r d i a l mass a n d r e g i o n a l c o r o n a r y b l o o d f l o w . H o w e v e r , t h e s c a n s w e r e o f i n f e r i o r q u a l i t y a n d s h o w e d a v a r i e t y o f s h a p e s o f t h e m y o c a r d i u m . Rb-81 i s t h e o n l y r a d i o n u c l i d e o f r u b i d i u m w h i c h h a s b e e n e f f e c t i v e l y i m a g e d ( M a r t i n e t a l . , 1 9 7 4 ) . R u b i d i u m - 8 1 h a s more f a v o r a b l e p h o t o n e n e r g i e s (511 K e V ) , a s h o r t e r h a l f - l i f e ( 4 . 6 h o u r s ) / a n d c a n be e c o n o m i c a l l y p r o d u c e d ( D w y e r , 1 9 7 5 ; M a r t i n e t a l . , 1 9 7 4 ) . I t d e c a y s by e l e c t r o n c a p t u r e t o K r y p t o n - 8 1 m , w h i c h ha.s; a 13 s e c o n d s h a l f - l i f e , a n d e m i t s a 190 KeV p h o t o n , w h i c h i s g o o d f o r t h e p r e s e n t i m a g i n g s y s t e m s a v a i l a b l e . W i t h t h e s e more f a v o r a b l e p h o t o n e n e r g i e s , 26 t h e r e i s l e s s l a t e r a l c o l l i m a t o r p e n e t r a t i o n a n d b e t t e r r e s o l u t i o n ( M a r t i n e t a l . , 1 9 7 4 ) . The s h o r t h a l f - l i f e a l l o w s s t u d i e s t o be a c c o m p l i s h e d a t s h o r t e r i n t e r v a l s w i t h o u t d e g r a d a t i o n o f i m a g e s d u e t o e x c e s s i v e b a c k g r o u n d a c t i v i t y ( M a r t i n e t a l . , 1 9 7 4 ) . Rb-81 c a n be u s e d f o r b o t h r e s t a n d e x e r c i s e m y o c a r d i a l i m a g i n g . C l i n i c a l s t u d i e s , e v e n t h o u g h p r o m i s i n g , a r e l i m i t e d d u e t o t h e s h o r t h a l f - l i f e a n d t h e n e e d f o r d a i l y s u p p l i e s f r o m a r e a c t o r . c ) C e s i u m C e s i u m h a s t h e l a r g e s t c r y s t a l r a d i u s o f t h e p o t a s s i u m a n a l o g s ( P a u l i n g , 1 9 6 9 ; L o v e e t a l . , 1 9 6 8 ) . I t r e q u i r e d a l o n g e r t i m e f o r c e s i u m t o r e a c h p e a k l e v e l s i n t h e m y o c a r d i u m a n d , a c c o r d i n g l y , i t was c l e a r e d more s l o w l y f r o m t h e m y o c a r d i u m a s w e l l a s t h e b l o o d ( P o e , 1 9 7 2 ) . A t o n e h o u r p o s t - i n j e c t i o n o f c e s i u m , a p p r o x i m a t e l y 5% o f t h e i n j e c t e d d o s e was c o n c e n t r a t e d i n t h e h e a r t , 9% i n t h e k i d n e y s , a n d 28% i n t h e G I T , w h i l e 2% r e m a i n e d i n * - t h e b l o o d s t r e a m ( M c A f e e and S u b r a m a n i a n , 1 9 7 5 ; M a t t h e w s e t a l . , 1 9 6 9 ) . The f u n c t i o n a l d i f f e r e n c e s b e t w e e n c e s i u m a n d p o t a s s i u m w e r e a t t r i b u t e d t o t h e l a r g e r c r y s t a l r a d i u s o f c e s i u m , w h i c h p r e s u m a b l y i n t e r f e r e d w i t h t h e t r a n s f e r o f t h e i o n a c r o s s t h e c e l l membrane ( P o e , 1 9 7 2 ; P a u l i n g , 1 9 6 9 ) . T h i s a c c o u n t e d f o r t h e l o w m y o c a r d i a l e x t r a c t i o n o f o n l y 22% a f t e r a s i n g l e c i r c u l a t i o n t h r o u g h t h e h e a r t ( L o v e e t a l . , 1 9 6 8 ) . C a r r e t a l . ( 1 9 6 3 ) h a v e shown m y o c a r d i a l i n f a r c t s a s i m a g i n g d e f e c t s a f t e r i n t r a v e n o u s a d m i n i s t r a t i o n o f C s - 1 3 1 i n d o g s . S c a n s w e r e p e r f o r m e d 1 - 3 h o u r s a f t e r i n j e c t i o n o f t h e r a d i o n u c l i d e . The 27 a n i m a l s w e r e . s a c r i f i c e d , t h e h e a r t s e x c i s e d , w a s h e d f r e e o f b l o o d , a n d r e s c a n n e d . I t was f o u n d t h a t t h e m y o c a r d i a l C s - 1 3 1 t o b l o o d r a t i o s i n c r e a s e d l i n e a r l y w i t h t i m e and a p p r o a c h e d 2 0 : 1 by 2 h o u r s ( C a r r e t a l . , 1 9 6 3 ) . T h e r e was a p r o n o u n c e d d e c r e a s e o f C s - 1 3 1 i n t h e i n f a r c t . I n v i e w o f t h e s u c c e s s o f t h e a n i m a l s t u d i e s , c l i n i c a l t r i a l s w e r e i n i t i a t e d by C a r r e t a l . ( 1 9 6 4 ) . A n t e r i o r m y o c a r d i a l i n f a r c t s w e r e d e m o n s t r a t e d a s i m a g i n g d e f e c t s a f t e r t h e i n t r a v e n o u s a d m i n i s t r a t i o n o f 2 . 5 mCi o f C s - 1 3 1 . H o w e v e r , t h e p r i n c i p a l e m i s s i o n s o f t h e r a d i o -n u c l i d e ( 3 0 KeV X e n o n - X - r a y s ) w e r e s o weak t h a t p o s t e r i o r m y o c a r d i a l i n f a r c t s c o u l d n o t be d e t e c t e d . The h e p a t i c u p t a k e a s w e l l a s t h e u p t a k e by t h e b o n y t h o r a x o b s c u r e d t h e a n t e r i o r p o r t i o n s o f t h e m y o c a r d i u m . F u r t h e r c l i n i c a l t r i a l s by McGeeham e t a l . ( 1 9 6 8 ) s h o w e d 8 o u t o f 9 i m a g i n g d e f e c t s w h i c h c o r r e l a t e d w e l l w i t h t h e l o c a t i o n s o f t h e i n f a r c t s a s i n d i c a t e d - b y ECG a n d c o r o n a r y a r t e r i o g r a m s . H o w e v e r , t h e e n e r g y o f C s - 1 3 1 , a l o n g w i t h t h e l o n g h a l f - l i f e o f n i n e d a y s , makes t h i s r a d i o n u c l i d e u n s u i t a b l e f o r e x t e r n a l i m a g i n g . Use o f o t h e r r a d i o i s o t o p e s o f c e s i u m h a v e a l s o b e e n r e p o r t e d . Yano e t a l . ( 1 9 7 0 ) u t i l i z e d t h e i m p r o v e d i m a g i n g c h a r a c t e r i s t i c s o f C s - 1 2 9 . I t h a s a h a l f - l i f e o f 32 h o u r s a n d d e c a y s 100% by e l e c t r o n c a p t u r e . The p h o t o p e a k s a r e f r o m 3 7 5 - 4 1 6 K e V . I n p r e l i m i n a r y s t u d i e s i n d o g s , m a j o r o r g a n s o f u p t a k e i n c l u d e d t h e h e a r t , l i v e r . , G I T , k i d n e y , l u n g s , a n d t h e s p l e e n . The h i g h e s t c o n c e n t r a t i o n was i n t h e GIT w h i l e t h e g r e a t e s t r a d i a t i o n e x p o s u r e was t o t h e k i d n e y s . The o p t i m a l m y o c a r d i a l s c a n t i m e was f o u n d t o be 4 0 - 9 0 m i n u t e s p o s t - i n j e c t i o n a n d 28 showed an a b s e n c e o f r a d i o n u c l i d e i n r e g i o n s o f i n f a r c t i o n s ( Y a n o e t a l . , 1 9 7 0 ) . C l i n i c a l e v a l u a t i o n by R o m i l t e t a l . ( 1 9 7 3 ) e x h i b i t e d v i s u a l d e f e c t s i n s c a n s o f p a t i e n t s w i t h m y o c a r d i a l i n f a r c t s . C s - 1 2 9 r e m a i n e d i n t h e m y o c a r d i u m l o n g e r t h a n t h e o t h e r p o t a s s i u m a n a l o g s a n d t h u s a l l o w e d s e r i a l i m a g i n g t o be p e r f o r m e d . B e c a u s e o f i t s l o w e r e n e r g y , t h e r e i s b e t t e r r e s o l u t i o n w i t h C s - 1 2 9 t h a n w i t h K - 4 3 . D e s p i t e t h e s e r e s u l t s , c e s i u m - 1 2 9 i s n o t w i d e l y u s e d d u e t o t h e l o w e x t r a c t i o n by t h e h e a r t , t h e h i g h u p t a k e by t h e G I T , t h e h i g h e x p o s u r e t o t h e k i d n e y s , a n d t h e l a c k o f a c o m m e r c i a l l y a v a i l a b l e s o u r c e . d) T h a l l i u m T h a l l i u m - 2 0 1 i s c u r r e n t l y t h e r a d i o n u c l i d e o f c h o i c e f o r m y o c a r d i a l p e r f u s i o n i m a g i n g ( P o e , 1 9 7 7 ; S t r a u s s a n d P i t t , 1 9 7 7 ) . A l t h o u g h t h a l l i u m ( T I ) i s n o t c h e m i c a l l y r e l a t e d t o p o t a s s i u m , i t i s s i m i l a r t o p o t a s s i u m i n t e r m s o f d i s t r i b u t i o n a n d n e u r o p h y s i o l o g y f u n c t i o n ( G e h r i n g a n d Hammond 1 9 6 7 ; M u l l i n s a n d M o o r e , 1 9 6 0 ) . The e x p l a n a t i o n f o r t h e b i o l o g i c a l s i m i l a r i t y o f t h a l l i u m t o p o t a s s i u m i s b a s e d on t h e i o n i c r a d i u s o f t h e s e e l e m e n t s . The h y d r a t e d i o n i c r a d i u s o f t h a l l i u m i s b e t w e e n t h a t o f p o t a s s i u m a n d r u b i d i u m , a n d t h i s r a d i u s h a s b e e n s u g g e s t e d a s t h e p r o p e r t y w h i c h d e t e r m i n e s p e n e t r a t i o n t h r o u g h a membrane ( B r i t t e n a n d B l a n k , 1 9 6 8 ) . T h a l l i u m - 2 0 1 d e c a y s by e l e c t r o n c a p t u r e a n d h a s a h a l f - l i f e o f 73 h o u r s ( L e b o w i t z e t a l . , 1 9 7 5 ) . I t e m i t s m e r c u r y X - r a y s o f 6 9 - 8 3 KeV i n 98% a b u n d a n c e p l u s gamma r a y s o f 135 and 167 KeV i n 10% 29 a b u n d a n c e ( L e b o w i t z e t a l . , 1 9 7 5 ) . The l o w e n e r g y 8 0 - K e V r a y s a r e s u b o p t i m a l a s t h e r e i s some l o s s o f s p a t i a l r e s o l u t i o n d u e t o i n c o m p l e t e e l i m i n a t i o n o f s c a t t e r e d r a d i a t i o n f r o m t h e p r i m a r y p h o t o p e a k by t h e p u l s e h e i g h t a n a l y s e r . H o w e v e r , T I - 2 0 1 i s a v a i l a b l e f r o m s e v e r a l c o m m e r c i a l s o u r c e s a n d c a n be s u c c e s s f u l l y v i s u a l i z e d w i t h t h e p r e s e n t l y a v a i l a b l e n u c l e a r i n s t r u m e n t s . A f t e r IV a d m i n i s t r a t i o n , T I - 2 0 1 i s d i s t r i b u t e d t h r o u g h o u t t h e w h o l e b o d y w h e r e i t i s e x t r a c t e d by v a r i o u s o r g a n s ( L e b o w i t z e t a l . , 1 9 7 5 ; S t r a u s s e t a l . , 1 9 7 5 ) . A b o u t 2 - 5 % o f t h e i n j e c t e d d o s e i s c o n c e n t r a t e d i n t h e h e a r t ( S t r a u s s a n d P i t t , 1 9 7 7 ) . T h a l l i u m h a s t h e h i g h e s t h e a r t / b l o o d a n d h e a r t / l i v e r r a t i o s c o m p a r e d t o t h e o t h e r p o t a s s i u m a n a l o g s ( J a n o w i t z e t a l . , 1 9 7 7 ; S t r a u s s e t a l . , 1 9 7 5 ) . The b l o o d c i r c u l a t i o n d e c r e a s e s i n an e x p o n e n t i a l m a n n e r t o 2 - 3 % o f t h e i n j e c t e d d o s e by 8 - 1 0 m i n u t e s ( S t r a u s s e t a l . , 1 9 7 5 ) . A c o m p a r i s o n o f t h e p l a s m a d i s a p p e a r a n c e o f T I - 2 0 1 a n d K - 4 3 s u g g e s t s t h e i o n i c movements a r e r e l a t e d ( G e h r i n g a n d Hammond, 1 9 6 7 ) . H o w e v e r , o n c e i n s i d e t h e c e l l , t h a l l i u m i s l e s s r e a d i l y r e l e a s e d t h a n p o t a s s i u m ( G e h r i n g a n d Hammond, 1 9 6 7 ) . T h a l l i u m i s p r o b a b l y e x t r a c t e d by t h e N a + - K + A T P a s e s y s t e m by b i n d i n g on 2 s i t e s o f t h e enzyme i n c o n t r a s t t o t h e s i n g l e b i n d i n g s i t e by p o t a s s i u m ( B r i t t e n and B l a n k , 1 9 6 8 ) . A l t h o u g h t h a l l i u m c a n c a u s e t o x i c e f f e c t s , t h e a d m i n i s t e r e d d o s e f o r i m a g i n g i s l e s s t h a n 1 0 , 0 0 0 t i m e s t h e m i n i m a l t o x i c d o s e ( J a n o w i t z e t a l . , 1 9 7 7 : L u n d , 1 9 5 6 ) . T h e r e i s no e v i d e n c e o f t o x i c i t y w i t h t h e c u r r e n t l y u s e d d o s a g e s o f t h a l l i u m . 30 Kawana et_a]_- ( 1 9 7 0 ) s u g g e s t e d t h e u s e o f T l - 1 9 9 a s a p o t a s s i u m a n a l o g f o r m y o c a r d i a l s c a n n i n g . H o w e v e r , t h e e n e r g y o f T l - 1 9 9 was u n s u i t a b l e f o r e x t e r n a l i m a g i n g . D i f f e r e n t r a d i o i s o t o p e s o f t h a l l i u m w e r e e v a l u a t e d by L e b o w i t z e t a l . ( 1 9 7 5 ) a n d t h e b e s t s p e c t r a l p r o p e r t i e s w e r e f o u n d t o b e l o n g t o T l - 2 0 1 . S t r a u s s e t a l . ( 1 9 7 5 ) a s s e s s e d r e g i o n a l m y o c a r d i a l d i s t r i b u t i o n i n d o g s c o m p a r i n g T l - 2 0 1 t o m i c r o s p h e r e s u n d e r c o n d i t i o n s o f p a r t i a l o c c l u s i o n a n d r e a c t i v e h y p e r e m i a . The c o r r e l a t i o n was g o o d a l t h o u g h t h a l l i u m r e q u i r e d a s h o r t b u t f i n i t e t i m e t o c l e a r f r o m t h e b l o o d a n d e n t e r i n t o t h e . - t i s s u e s . I n t h e a n i m a l s t u d i e s by J a m b r o e s e t a l . ( 1 9 7 5 ) i t a p p e a r e d t h a t m y o c a r d i a l i n f a r c t s s h o u l d i n v o l v e 10% o f t h e m y o c a r d i u m i n o r d e r t o be v i s u a l i z e d i n t h e b e a t i n g h e a r t . B r a d l e y - M o o r e e t a l . ( 1 9 7 5 ) d i d c o m p r e h e n s i v e s t u d i e s on t h e b i o l o g i c a l b e h a v i o r o f T l - 2 0 1 i n g o a t s w i t h c o r o n a r y i n f a r c t i o n s . T h e y f o u n d t h e h a l f - t i m e i n t h e h e a r t t o c o n s i s t o f 2 c o m p o n e n t s . D o c u m e n t e d c l i n i c a l t r i a l s w e r e i n i t i a l l y d o n e by W a c k e r s e t a l . ( 1 9 7 5 ) . T h e s e t r i a l s s h o w e d T l - 2 0 1 t o be o f d i a g n o s t i c v a l u e f o r i d e n t i -f i c a t i o n o f a c u t e m y o c a r d i a l i n f a r c t s . A l l t h e p a t i e n t s w i t h m y o c a r d i a l i n f a r c t s had m y o c a r d i a l s c a n s w i t h d i m i n i s h e d r a d i o a c t i v i t y a t t h e a r e a c o r r e s p o n d i n g t o t h e e l e c t r o c a r d i o g r a p h i c l o c a l i z a t i o n o f t h e i n f a r c t . Due t o t h e s u c c e s s o f t h e i n i t i a l c l i n i c a l t r i a l s , more e x t e n s i v e c l i n i c a l t r i a l s w e r e u n d e r t a k e n t o e v a l u a t e t h e v a l u e a n d l i m i t a t i o n s o f t h a l l i u m - 2 0 1 i n m y o c a r d i a l s c a n n i n g ( W a c k e r s e t a l . , 1 9 7 6 ) . O f t h e 2 0 0 p a t i e n t s s t u d i e d , d e f e c t i v e s c a n s w e r e f o u n d i n 165 p a t i e n t s . 31 H o w e v e r , t h e d i a g n o s t i c a c c u r a c y was h i g h e r , 94% i n t h o s e p a t i e n t s who w e r e s c a n n e d w i t h i n 24 h o u r s a f t e r t h e o n s e t o f p a i n . The a d v a n t a g e o f T I - 2 0 1 i n c l u d e d t h e e a r l y and p r e c i s e a n a t o m i c l o c a l i z a t i o n o f t h e i n f a r c t . T I - 2 0 1 i s h i n d e r e d , h o w e v e r , by i t s i n a b i l i t y t o d i f f e r e n t i a t e b e t w e e n r e c e n t and o l d i n f a r c t s ( W a c k e r s e t a l . , 1 9 7 6 ) . I n an e f f o r t t o i m p r o v e t h e q u a l i t y o f t h e T I - 2 0 1 s c a n s , Cook e t a l . ( 1 9 7 6 ) i m a g e d h e a l t h y p a t i e n t s a f t e r t r a c e r a d m i n i s t r a t i o n , b o t h a t r e s t a n d a t m a x i m a l s t r e s s . The r e s t s c a n s s h o w e d T I - 2 0 1 u p t a k e by t h e l e f t v e n t r i c l e , l i v e r , a n d s p l e e n w h i l e t h e e x e r c i s e s c a n s s h o w e d a more homogeneous l e f t v e n t r i c l e and b e t t e r d e f i n i t i o n o f t h e r i g h t v e n t r i c l e . A m e t h o d t o a u g m e n t m y o c a r d i a l T I - 2 0 1 u p t a k e u s i n g s o d i u m b i c a r b o n a t e h a s b e e n d e v i s e d ( H e t z e l e t a l . , 1 9 7 7 ) . I n v i v o i m a g i n g o f d o g s s h o w e d a 1 . 5 - 2 t i m e s i n c r e a s e o f t h a l l i u m i n t h e h e a r t a n d a t h r e e t i m e s e n h a n c e m e n t o f h e a r t t o l i v e r u p t a k e . The e x a c t m e t h o d b y w h i c h b i c a r b o n a t e a l t e r e d t h e d i s t r i b u t i o n o f t h a l l i u m h a s n o t b e e n f u l l y e l u c i d a t e d . R e c e n t l y , W a t s o n e t a l . ( 1 9 7 8 ) d e r i v e d a m u l t i - c o m p a r t m e n t model f o r t h e i n v i v o d i s t r i b u t i o n o f t h a l l i u m . The m o d e l i n d i c a t e d a t h r e e p h a s e t h a l l i u m u p t a k e . The u s e f u l n e s s o f T I - 2 0 1 i n s t r e s s s c i n t i g r a p h y t o c l a r i f y e q u i v o c a l e l e c t r o c a r d i o g r a m s when c h e s t p a i n was p r e s e n t was d e m o n s t r a t e d by B o t v i n i c k e t a l . , . ( 1 9 7 8 ) . S t r e s s s c a n s i d e n t i f i e d t h e c o r o n a r y c a u s e s o f c h e s t p a i n t o be due t o l e f t b u n d l e b r a n c h b l o c k . 32 The s e n s i t i v i t y o f m y o c a r d i a l i m a g i n g w i t h T l - 2 0 1 f o r r e p r o d u c i b l e i m a g e i n t e r p r e t a t i o n was t e s t e d among 4 e x p e r i e n c e d r e a d e r s a t 2 d i f f e r e n t i n s t i t u t i o n s ( T r o b a u g h e t a l . , 1 9 7 8 ) . Of 100 s c a n s o f m y o c a r d i a l i n f a r c t i o n o r i s c h e m i a , t h e r e was c o m p l e t e a g r e e m e n t i n 79 s c a n s , m i n o r d i s a g r e e m e n t i n 8 s c a n s . , a n d m a j o r d i s a g r e e m e n t i n 13 s c a n s . T h u s , t h e i n t e r o b s e r v e r d i s a g r e e m e n t f o u n d s u g g e s t v a r i a b i l i t y i n r e a d i n g a n d i n t e r p r e t a t i o n o f u n p r o c e s s e d s c a n s . e ) R a d i o i o d i n a t e d F a t t y A c i d s B i o c h e m i c a l s u b s t r a t e s s u c h as f a t t y a c i d s h a v e p r o v e n t o be u s e f u l f o r m y o c a r d i a l i m a g i n g . T h e s e w i l l be d i s c u s s e d i n a l a t e r s e c t i o n . f ) F u t u r e T r e n d s S h o r t - l i v e d p o s i t r o n e m i t t e r s s u c h as N i t r o g e n - 13 a n d C a r b o n ^ l l h a v e a l s o b e e n i n v e s t i g a t e d f o r m y o c a r d i a l i m a g i n g . H o w e v e r , t h e a d v a n t a g e s , as w e l l as t h e d i s a d v a n t a g e s o f t h e s e a g e n t s a r e b a s e d m a i n l y on t h e i r e x t r e m e l y s h o r t h a l f - l i v e s . 1 3 ( i ) N - a m m o n i a 13 N-ammonia was i n t r o d u c e d a s a p h y s i o l o g i c r a d i o t r a c e r f o r n u c l e a r m e d i c i n e by H u n t e r and Monahan ( 1 9 7 1 ) . N - 1 3 h a s a h a l f - l i f e o f 9 . 9 6 m i n u t e s a n d d e c a y s by p o s i t r o n e m i s s i o n ( H u n t e r a n d M o n a h a n , 1 9 7 1 ) . 1 3 I n i t i a l s t u d i e s u s i n g N-ammonia d e m o n s t r a t e d g o o d q u a l i t y m y o c a r d i a l s c a n s i n p a t i e n t s w i t h m a l i g n a n t n e o p l a s m s . S u b s e q u e n t c l i n i c a l t r i a l s by H a r p e r e t a l . ( 1 9 7 2 ) d e m o n s t r a t e d t h e f e a s i b i l i t y o f m y o c a r d i a l i m a g i n g 1 3 w i t h NH^. I n t h e s e human s t u d i e s , t h e b r a i n , l i v e r , k i d n e y a n d b l a d d e r w e r e a l s o i m a g e d (Hoop e t a l . , 1 9 7 3 ; H a r p e r e t a l . , 1 9 7 2 ) . 33 The m y o c a r d i a l u p t a k e o f '^NH^ was r a p i d f o l l o w i n g d i r e c t , a r t e r i a l i n j e c t i o n , a n d g r e a t e r t h a n 90% e x t r a c t i o n was d e m o n s t r a t e d a f t e r a s i n g l e p a s s a g e t h r o u g h t h e dog h e a r t ( H a r p e r e t a l . , 1 9 7 3 ) . O n l y 15% o f t h e t r a c e r r e m a i n e d i n t h e b l o o d p o o l a f t e r t h e f i r s t m i n u t e ( H a r p e r e t a l . , 1 9 7 2 ) . A b o u t 15% o f t h e i n j e c t e d d o s e was c o n c e n t r a t e d i n t h e l i v e r . P u l m o n a r y u p t a k e was e a r l y and t r a n s i e n t , e x c e p t i n c h r o n i c s m o k e r s ( H a r p e r e t a l . , 1 9 7 3 ) . I n c l i n i c a l t r i a l s o f 22 i n f a r c t p a t i e n t s s t u d i e d by H a r p e r e t a l . ( 1 9 7 3 ) , s u c c e s s f u l s c a n s d e f i n i t e l y i n d i c a t i v e ' o f m y o c a r d i a l i n f a r c t s w e r e o b t a i n e d i n 17 p a t i e n t s , w h i l e 2 s c a n s s h o w e d p o s s i b l e i n f a r c t and 3 s c a n s w e r e n e g a t i v e . W a l s h a n d R e s n e k o v ( 1 9 7 6 ) e v a l u a t e d m y o c a r d i a l p e r f u s i o n i n 13 112 p a t i e n t s w i t h NH^. S u c c e s s f u l i m a g i n g was o b t a i n e d a s t h e b l o o d c l e a r a n c e o f t h e t r a c e r was r a p i d . A b o u t 2 - 4 % o f t h e i n j e c t e d d o s e was t a k e n up by t h e m y o c a r d i u m w h e r e i t r e m a i n e d f o r up t o 30 m i n u t e s ( W a l s h a n d R e s n e k o v , 1 9 7 6 ) . The a m m o n i a - w a s m a i n l y i n t h e i o n i z e d c a t i o n i c f o r m i n p h y s i o l o g i c pH and was t h e r e f o r e i m p e r m e a b l e t o c e l l membranes ( W a l s h e t a l . , 1 9 7 7 ; W a l s h a n d R e s n e k o v , 1976) . The m e c h a n i s m o f u p t a k e o f t h e ammonium i o n h a s n o t b e e n e l u c i d a t e d b u t t h e r a p i d b l o o d c l e a r a n c e s u g g e s t e d a d i f f e r e n t m e t h o d f r o m t h a t o f t h e p o t a s s i u m a n a l o g s . Once i n c o r p o r a t e d i n t o t h e m y o c a r d i a l c e l l s , t h e ammonium i o n was m e t a b o l i z e d v i a t h e g l u t a m i n e s y n t h e t a s e p a t h w a y t o g l u t a m i n e , w h i c h t h e n e n t e r e d t h e a m i n o a c i d p o o l ( W a l s h e t a l . , 1 9 7 7 ) . S u b s e q u e n t s t u d i e s a t s h o r t i n t e r v a l s a f t e r AMI s h o w e d g o o d c o r r e l a t i o n b e t w e e n t h e ECG s i t e o f 13 i n f a r c t a n d t h e p e r f u s i o n d e f e c t on t h e NH^ s c a n ( W a l s h e t a l . , 1 9 7 7 ) . 34 The l i m i t a t i o n s o f '""NH^ i n c l u d e t h e n e c e s s i t y o f an o n - s i t e •13 c y c l o t r o n and a p o s i t r o n c a m e r a . G e n e r a l l y , i n t h e '» Nh^ s c a n s , o v e r l a p p i n g r e g i o n s o f t h e h e a r t c o u l d n o t be s e p a r a t e d a n d a c t i v i t y i n t h e more d i s t a n t r e g i o n s was n o t r e a d i l y d e t e c t e d ( W a l s h e t a l . , 1 9 7 7 ) . ( i i ) ^ C - p a l m i t a t e and ^ C - o c t a n o a t e C a r b o n - 1 1 h a s a h a l f - l i f e o f 2 0 . 3 m i n u t e s a n d d e c a y s by p o s i t r o n e m i s s i o n ( W e i s s e t a l . , 1 9 7 6 ) . I t h a s b e e n u s e d t o l a b e l v a r i o u s f a t t y a c i d s f o r m y o c a r d i a l s t u d i e s . W e i s s e t a l . ( 1 9 7 6 ) s c a n n e d d o g s w i t h a n d w i t h o u t i n d u c e d . ' i s c h e m i a a f t e r t h e i n t r a v e n o u s a d m i n i s t r a t i o n o f ^ C - p a l m i t a t e u s i n g ECG g a t e d p o s i t r o n - e m i s s i o n t r a n s a x i a l t o m o g r a p h y . T h e r e was d i m i n i s h e d ^ C - p a l m i t a t e u p t a k e i n z o n e s o f i s c h e m i a . S u b s e q u e n t l y W e i s s e t a l . ( 1 9 7 7 ) q u a n t i f i e d c r o s s s e c t i o n s o f c a n i n e m y o c a r d i u m i n v i v o u s i n g ^ C - p a l m i t a t e w i t h p o s i t r o n t r a n s a x i a l t o m o g r a p h y and c o m p a r e d t h e r e s u l t s w i t h r e g i o n a l m y o c a r d i a l CRK d e p l e t i o n . The c a n i n e s t u d i e s s h o w e d CPK a c t i v i t y t o p a r a l l e l t h e ^ C - p a l m i t a t e d e c r e a s e i n t h e i s c h e m i c z o n e . The p e r c e n t a g e i n f a r c t i o n i n t h e t o m o -g r a p h i c c r o s s s e c t i o n s c o r r e l a t e d w e l l w i t h i n f a r c t i o n i n t h e c o r r e s p o n d i n g c r o s s s e c t i o n s f r o m t h e same h e a r t e s t i m a t e d m o r p h o m e t r i c a l l y a n d by CPK d e p l e t i o n . ( W e i s s e t a l . , 1 9 7 7 ) . The s t u d i e s o f H o f f m a n e t a l . ( 1 9 7 7 ) showed s i m i l a r t o m o g r a p h i c i m a g e s . I n s p i t e o f t h e s e p r o m i s i n g r e s u l t s , t h e m a j o r d r a w b a c k i s t h a t C a r b o n - 1 1 w i l l n e v e r be g e n e r a l l y a v a i l a b l e . 4 . F a t t y A c i d s The n a t u r a l l y o c c u r i n g f a t t y a c i d s a r e u s u a l l y s t r a i g h t ^ c h a i n e d , 35 e v e n - n u m b e r e d , m o n o - c a r b o x y l i c a c i d s w i t h t h e g e n e r a l f o r m u l a : C H 3 ( C H 2 ) n C 0 0 H ( S a c k h e i m . a n d S e h u l t z , . 1 9 7 7 ; R o u t h e t a l . , 1 9 7 3 ) . T h e s e o r g a n i c a c i d s may be s a t u r a t e d o r u n s a t u r a t e d a n d a r e a c o n s t i t u e n t o f t h e d a i l y d i e t a r y f a t s . I n g e s t e d f a t s a r e e m u l s i f i e d i n t h e s t o m a c h , f o l l o w e d by d i g e s t i o n by b i l e s a l t s , p a n c r e a t i c j u i c e s , and chyme i n t h e s m a l l i n t e s t i n e s ( S a c k h e i m a n d S e h u l t z , 1 9 7 7 ; G u n s t o n e , 1 9 6 7 ) . D i g e s t i o n i n v o l v e s h y d r o l y s i s o f f a t s t o f a t t y a c i d s a n d g l y c e r o l s . M o s t o f t h e g l y c e r o l a n d any s h o r t c h a i n a c i d s p a s s t o t h e p o r t a l b l o o d w h i l e m o n o g l y c e r i d e s a n d l o n g e r c h a i n f a t t y a c i d s p a s s t h r o u g h t h e l a c t e a l s o f t h e v i l l i i n t o t h e l y m p h a t i c s , w h e r e t h e y a p p e a r a s r e s y n t h e s i z e d f a t s . T h e s e t h e n ; p a s s i n t o t h e g e n e r a l c i r c u l a t i o n v i a t h e t h o r a c i c d u c t a n d a r e t r a n s p o r t e d by t h e b l o o d s t r e a m t o t h e l i v e r ( 3 0 % ) , f a t d e p o t s (30%) m u s c u l a t u r e a n d o t h e r o r g a n s (40%) ( G u n s t o n e , 1 9 6 7 ) . B l o o d l i p i d l e v e l s may f l u c t u a t e r e f l e c t i n g t h e d y n a m i c p r o c e s s e s i n v o l v e d . C i r c u l a t i n g l i p i d l e v e l s a r e i n c r e a s e d by i n t e s t i n a l a b s o r p t i o n , by s y n t h e s i s , o r by r e l e a s e f r o m a d i p o s e t i s s u e , w h i l e t h e y a r e a l t e r -n a t i v e l y d e c r e a s e d by s t o r a g e i n f a t d e p o t s , o x i d a t i o n , a n d s y n t h e s i s o f s t r u c t u r a l c o m p o n e n t s o f c e l l s ( F r e d r i c k s o n a n d G o r d o n , 1 9 5 8 ) . The b l o o d l i p i d s c o n s i s t s o f t r i g l y c e r i d e s , p h o s p h o l i p i d s as w e l l as c h o l e s t e r o l w h i c h a r e c o m b i n e d a s l i p o p r o t e i n c o m p l e x e s . S m a l l a m o u n t s o f f r e e f a t t y a c i d s a r e a l s o p r e s e n t i n t h e b l o o d a n d e x i s t m a i n l y as a l b u m i n - b o u n d f r e e f a t t y a c i d s ( F F A ) ( G o o d m a n , 1 9 5 8 a ; G o r d o n e t a l . , 1 9 5 7 ; G o r d o n a n d C h e r k e s , 1 9 5 6 ; D o l e , 1 9 5 6 ) . T h i s a l b u m i n - b o u n d FFA i s t h e p r i n c i p a l f o r m by w h i c h d e p o t f a t i s t r a n s p o r t e d t o v a r i o u s t i s s u e s f o r o x i d a t i o n . I t i s e s s e n t i a l f o r f a t t y a c i d s t o be i n t h e f r e e o r u n e s t e r i f e d 36 f o r m i n o r d e r t o be o x i d i z e d . ( S p e c t o r , 1 9 6 8 ; W a s s e r m a n a n d M e y e r s o n , 1 9 5 1 ) . O x i d a t i v e d e g r a d a t i o n o f f a t t y a c i d s i s a u n i v e r s a l b i o c h e m i c a l c a p a c i t y among l i v i n g o r g a n i s m s ( C h a p m a n , 1 9 6 9 ) . I n m a m m a l s , s u c h o x i d a t i o n o c c u r s i n t h e l i v e r , t h e k i d n e y s , a n d t h e h e a r t . I n t r a c e l l u l a r ^ , f a t t y a c i d o x i d a t i o n o c c u r s p r i n c i p a l l y i n t h e m i t o c h o n d r i a . F a t t y a c i d s a r e t h e m o s t a c t i v e f o r m o f l i p i d s i n v o l v e d i n m e t a b o l i s m ( S a c k h e i m - a n d S c h u l t z , 1 9 7 7 ) . F a t t y a c i d s c o n t a i n more s t o r e d f o o d e n e r g y p e r c a r b o n a t o m t h a n any o t h e r b i o l o g i c a l f u e l ( F r e d r i c k s o n a n d G o r d o n , 1 9 5 8 ) . T h e y a r e d e g r a d e d by e n z y m a t i c p r o c e s s e s t o e n d p r o d u c t s o f c a r b o n d i o x i d e , w a t e r a n d e n e r g y s t o r e d as a d e n o s i n e t r i p h o s p h a t e (ATP) ( R o u t h e t a l . , 1 9 7 3 ) . I t has b e e n e s t i m a t e d t h a t 88% o f t h e r e l e a s e d e n e r g y i s t r a p p e d by t h e c o m p l e t e o x i d a t i o n o f o n e m o l e o f p a l m i t i c a c i d ( G u n s t o n e , 1 9 6 7 ) . a ) M y o c a r d i a l M e t a b o l i s m Two t h i r d s o f t h e t o t a l d a i l y m y o c a r d i a l c o n s u m p t i o n h a s b e e n a t t r i b u t e d t o t h e o x i d a t i o n o f p l a s m a f r e e f a t t y a c i d s ( O l i v e r , 1 9 7 6 ; S p i t z e r a n d S p i t z e r , 1 9 7 1 ; R o t h l i n a n d B i n g , 1 9 6 1 ) . O t h e r s u b s t r a t e s u t i l i z e d by t h e h e a r t i n c l u d e g l u c o s e , 1 5 % , l a c t a t e and p y r u v a t e , 12%, . a m i n o a c i d s , 5 % , a n d t h e b a l a n c e c o n s i s t i n g o f k e t o n e b o d i e s , t r i g l y c e r i d e s , a n d g l y c e r o l s ( O l i v e r , 1 9 7 6 ) . A d i r e c t c o r r e l a t i o n h a s b e e n o b s e r v e d b e t w e e n t h e m y o c a r d i a l o x y g e n c o n s u m p t i o n a n d f r e e f a t t y a c i d o x i d a t i o n ( S p i t z e r a n d S p i t z e r , 1 9 7 1 ; C o w l e y e t a l . , 1 9 6 9 ; C a r l s t e n e t a l . , 1 9 6 3 ) . P l a s m a f r e e f a t t y a c i d c o n c e n t r a t i o n h a s b e e n f o u n d t o be i n t h e r a n g e o f . 3 7 t o 1.23mM i n h e a l t h y humans ( R o t h l i n a n d B i n g , 1 9 6 1 ; B a l l a r d e t a l . , I 9 6 0 ; G o r d o n a n d C h e r k e s , 1 9 5 6 ) . U n d e r p h y s i o l o g i c 37 c o n d i t i o n s , t h e m o l a r r a t i o o f F F A / a l b u m i n was f o u n d t o v a r y f r o m . 3 t o 1 . 8 ( G i l b e r t s o n , 1 9 7 7 ; R o t h l i n and B i n g , 1 9 6 1 ) . F a t t y a c i d s f o u n d i n human p l a s m a c o n s i s t e d o f s a t u r a t e d a c i d s f r o m 10 t o 18 c a r b o n s a s w e l l as o l e i c , p a l m i t o l e i c , l i n o l e i c , a n d l o n g e r c h a i n p o l y e t h e n o i c a c i d s ( W i l l e b r a n d , 1 9 6 4 ; F r e d r i c k s o n a n d G o r d o n , 1 9 5 8 ) . A n a l y s i s o f p l a s m a FFA by a r t e r i o v e n o u s d i f f e r e n c e s by R o t h l i n and B i n g ( 1 9 6 1 ) d e m o n s t r a t e d o l e i c a c i d (50%) t o be t h e l a r g e s t c o m p o n e n t , f o l l o w e d by p a l m i t i c a c i d . ( 2 8 . 3 % ) . An e s t i m a t e d t u r n - o v e r r a t e o f 2 0 - 4 0 % p e r m i n u t e was c a l c u l a t e d f o r p l a s m a FFA ( D o l e and R i z a c k , 1 9 6 1 ) . T h i s r a p i d t u r n - o v e r h a s b e e n a t t r i b u t e d p r i m a r i l y t o . t h e a v i d e x t r a c t i o n o f FFA by t h e w o r k i n g t i s s u e s . P l a s m a f r e e f a t t y a c i d s a r e d e r i v e d a l m o s t e x c l u s i v e l y f r o m a d i p o s e t i s s u e s ( E v a n s , 1 9 6 4 ) . M o b i l i z a t i o n o f f a t t y a c i d s f r o m t h e a d i p o s e t i s s u e was f o u n d t o be r e g u l a t e d by d i e t a r y , h o r m o n a l , and n e r v o u s s t i m u l i ( S p e c t o r , 1 9 6 8 ; E v a n s , 1 9 6 4 ) . H o r m o n e s s u c h as e p i n e p h r i n e , n o r e p i n e p h r i n e , a n d ACTH i n c r e a s e d m o b i l i z a t i o n w h i l e g l u c o s e a n d i n s u l i n d e c r e a s e d m o b i l i z a t i o n ( E v a n s , 1 9 6 4 ; G o r d o n e t a l . , 1 9 5 7 ) . ( i ) P e n e t r a t i o n o f P l a s m a F r e e F a t t y A c i d s i n t o C e l l s U n d e r p h y s i o l o g i c c o n c e n t r a t i o n s a n d p H , a l m o s t a l l o f t h e p l a s m a FFA i s i o n i z e d a n d b o u n d t o a l b u m i n ( F r e d r i c k s o n a n d G o r d o n , 1 9 5 8 ) . H o w e v e r , t h e b o u n d a n d u n b o u n d f o r m s e x i s t i n a n e q u i l i b r i u m a n d c i r c u n v s t a n t i a l e v i d e n c e s u g g e s t s t h a t i t i s t h e u n b o u n d FFA w h i c h g a i n s e n t r y i n t o t h e c e l l s by s i m p l e d i f f u s i o n ( K u r e i n a n d O l i v e r , 1 9 7 1 ; S p i t z e r and S p i t z e r , 1 .971; S p e c t o r e t a l . , 1 9 6 5 a ) . The m a g n i t u d e o f FFA u p t a k e has b e e n shown t o be 100% i n e x c e s s o f t h e u p t a k e o f a l b u m i n ( W a s s e r m a n a n d 38 M e y e r s o n , 1 9 5 1 ) . I t h a s b e e n p o s t u l a t e d t h a t a l b u m i n f a c i l i t a t e s FFA u p t a k e by some i n t e r a c t i o n w i t h t h e c e l l membrane a l t h o u g h FFA u p t a k e was o b s e r v e d i n t h e a b s e n c e o f a l b u m i n i n l o w e r y e t s i m i l a r l i n e a r r e l a t i o n -s h i p s ( S p e c t o r e t a l . , 1 9 6 5 a ) . As t h e u n b o u n d FFA i s t a k e n up by t h e c e l l , f r e e f a t t y a c i d d i s s o c i a t e s f r o m t h e a l b u m i n - c o m p l e x t o m a i n t a i n t h e e q u i l i b r i u m b e t w e e n t h e b o u n d a n d u n b o u n d f o r m s . F r e e f a t t y a c i d s d i f f u s e i n t o t h e u t i l i z i n g c e l l s due t o a c o n c e n t r a t i o n g r a d i e n t m a i n t a i n e d by t h e r a p i d m e t a b o l i s m o f t h e FFA ( S p e c t o r , 1 9 6 8 ) . T h i s e n e r g y - i n d e p e n d e n t t r a n s p o r t o f FFA i n t o t h e c e l l s was d e m o n s t r a t e d by t h e f a c t t h a t m e t a b o l i c i n h i b i t o r s s u c h as c y a n i d e a n d 2 - 4 d i n i t r o p h e n o l d i d n o t d e c r e a s e c e l l u l a r i n c o r p o r a t i o n o f 1 4 C - p a l m i t a t e ( S p e c t o r a n d S t e i n b e r g , 1 9 6 5 b ) . The FFA was l o c a t e d w i t h i n t h e s a r c o p l a s m i c r e t i c u l u m as w e l l as t h e m i t o c h o n d r i a . The d i f f u s i o n p r o c e s s w a s , i n a d d i t i o n t o b e i n g e n e r g y i n d e p e n d e n t , r e v e r s i b l e . S p e c t o r e t a l . ( 1 9 6 5 a ) d e m o n s t r a t e d t h e r e v e r s i b i l i t y by i n c u b a t i o n o f c e l l s i n a l a b e l e d FFA s o l u t i o n , w a s h i n g , a n d r e i n c u b a t i o n i n a s e c o n d medium w i t h a l b u m i n . R e l e a s e o f l a b e l e d FFA was f o u n d t o be d e p e n d e n t on t h e a l b u m i n c o n c e n t r a t i o n o f t h e m e d i u m , v a r y i n g f r o m 4 5 - 7 0 % o f t h e i n c o r p o r a t e d FFA. T h i s e x c h a n g e a b l e l a b e l e d FFA was l o c a t e d n e a r t h e c e l l m e m b r a n e . R e l e a s e o f f a t t y a c i d was a l s o o b s e r v e d d u r i n g i n c u b a t i o n w i t h m e t a b o l i c i n h i b i t o r s a s w e l l as i n c u b a t i o n a t l o w t e m p e r a t u r e s ( S p e c t o r , 1 9 7 1 ) . b) M y o c a r d i a l E x t r a c t i o n The m y o c a r d i a l e x t r a c t i o n o f FFA was f o u n d t o be d e p e n d e n t o n ( i ) t h e c i r c u l a t i n g FFA c o n c e n t r a t i o n , ( i i ) t h e F F A / a l b u m i n m o l a r r a t i o , 39 a n d ( i i i ) t h e c h a i n l e n g t h a n d d e g r e e o f u n s a t u r a t i o n o f t h e f a t t y a c i d ( E v a n s , 1 9 6 4 ) . ( i ) The C i r c u l a t i n g FFA c o n c e n t r a t i o n I n i n i t i a l s t u d i e s o f FFA u t i l i z a t i o n , a r t e r i a l - v e n o u s d i f f e r e n c e s i n d i c a t e d t h a t u p t a k e o f FFA was d e p e n d e n t o n p l a s m a c o n c e n t r a t i o n s o f t h e f a t t y a c i d s ( G i l b e r t o n , 1 9 7 7 ; C a r l s t e n e t a l . , 1 9 6 1 ; B a l l a r d e t a l . , I 9 6 0 ) : P a l m i t i c a n d o l e i c a c i d s w e r e t a k e n up t o a g r e a t e r e x t e n t t h a n s t e a r i c a n d l i n o l e i c a c i d s due t o t h e i r h i g h e r a r t e r i a l c o n c e n t r a t i o n s . ' H o w e v e r , t h e f r a c t i o n a l u p t a k e o f t h e f a t t y a c i d s was e s s e n t i a l l y t h e s a m e , t h u s i n d i c a t i n g t h a t p r e f e r e n t i a l u p t a k e d i d n o t o c c u r ( M i l l e r e t a l . , 1 9 6 2 ) . G o l d a n d S p i t z e r e v a l u a t e d a r t e r i a l - v e n o u s d i f f e r e n c e s f o r i n d i v i d u a l f a t t y a c i d s u s i n g t i t r a t i o n a n d l i q u i d s c i n t i l l a t i o n a n d f o u n d t h a t t h e n e t u p t a k e o f p l a s m a FFA o c c u r e d i n t h e h e a r t ( . l 9 6 4 ) . T h e r e a p p e a r e d t o be a FFA t h r e s h o l d o f a b o u t .350mM a r t e r i a l F F A , b e l o w w h i c h t h e r e was no e v i d e n c e o f m y o c a r d i a l e x t r a c t i o n by t h e human h e a r t ( C a r l s t e n e t a l . , 1 9 6 3 ) . S t u d i e s by G o r d o n a n d C h e r k e s ( 1 9 5 6 ) , S c o t t e t a l . ( 1 9 6 2 ) , a n d B a l l a r d e t a l . ( 1 9 6 0 ) a l s o i n d i c a t e d t h e e x i s t a n c e o f a FFA t h r e s h o l d , a l t h o u g h t h e t h r e s h o l d was v a r i a b l e . ( i i ) The M o l a r R a t i o o f F F A / A l b u m i n U t i l i z a t i o n o f ^ C - p a l m i t a t e by v a r i o u s c u l t u r e d c e l l p r e p a r a t i o n s i n c l u d i n g s k e l e t a l m u s c l e , e r y t h r o c y t e s , a n d h e a r t m u s c l e w e r e shown t o be i n v e r s e l y r e l a t e d t o t h e a l b u m i n p r e s e n t ( R e s h e f a n d S h a p i r o , 1 9 6 2 ; F r i t z and K a p l a n , 1 9 6 0 ; F r i t z , 1 9 5 9 ) . I n i s o l a t e d h e a r t p r e p a r a t i o n s , t h e u p t a k e o f ^ C - p a l m i t a t e i n c r e a s e d a s t h e m o l a r r a t i o o f F F A / a l b u n i n i n c r e a s e d ( E v a n s e t a l . , 1 9 6 3 a ) . When t h e m o l a r r a t i o 40 was d e c r e a s e d b y m a i n t a i n i n g a c o n s t a n t FFA c o n c e n t r a t i o n w h i l e i n c r e a s i n g t h e a l b u m i n c o n c e n t r a t i o n , t h e FFA u p t a k e d e c r e a s e d . S i m i l a r r e s u l t s w e r e o b t a i n e d i n a s e r i e s o f e x p e r i m e n t s b y , S p e c t o r e t v . a l . i n 1 9 6 5 . An i n c r e a s e i n t h e m o l a r r a t i o o f F F A / a l b u m i n was a c c o m p a n i e d by an e x p o n e n t i a l i n c r e a s e i n u p t a k e . The u p t a k e c a p a c i t y o f FFA d i d n o t a p p e a r s a t u r a t e d e v e n a t h i g h m o l a r r a t i o s , t h u s i n d i -c a t i n g t h a t t h e r a t e l i m i t i n g s t e p i n FFA o x i d a t i o n was n o t u p t a k e , b u t r a t h e r a s a t u r a t i o n o f t h e t r i c a r b o x y l i c a c i d c y c l e ( S p e c t o r , 1 9 6 8 ) . I t m u s t be k e p t i n m i n d t h a t t h e F F A / a l b u m i n r a t i o s u n d e r c o n s i d e r a t i o n i n m o s t e x p e r i m e n t s w e r e u n p h y s i o l o g i c a l l y h i g h , a n d t h a t u n d e r n o r m a l p h y s i o l o g i c c o n d i t i o n s , b l o o d a l b u m i n h a s s u f f i c i e n t f i r s t c l a s s b i n d i n g s i t e s f o r t h e FFA p r e s e n t i n t h e c i r c u l a t i o n ( G o o d m a n , 1 9 5 8 a ) . ( i i i ) C h a i n L e n g t h a n d t h e D e g r e e o f U n s a t u r a t i o n The m o l e c u l a r s t r u c t u r e was f o u n d t o a f f e c t t h e c e l l u l a r t r a n s p o r t a n d u t i l i z a t i o n o f f a t t y a c i d s . The p K a ' s o f f a t t y a c i d s a r e b e t w e e n 4 . 7 a n d 5 . 0 . T h u s , a t p h y s i o l o g i c p H , f a t t y a c i d s e x i s t a s a n i o n s ( G o o d m a n , 1 9 5 8 a ) . The e x i s t a n c e o f t h e s e f a t t y a c i d a n i o n s a p p e a r e d t o be e s s e n t i a l f o r b i n d i n g t o a l b u m i n ( S p e c t o r , 1 9 6 8 ) . F a t t y a c i d a n i o n s o f l o w a n d medium l e n g t h i n c r e a s e d t h e e l e c t r o p h o r e t i c m o b i l i t y o f s e r u m a l b u m i n , t h e r e b y - s u g g e s t i n g t h e f o r m a t i o n o f a f a t t y - a c i d a l b u m i n c o m p l e x ( B a l l o u e t a l . , 1 9 4 5 ) . I n P l a s m a , o v e r 99% o f t h e f r e e f a t t y a c i d s e x i s t a s a bound c o m p l e x t o a l b u m i n ( T e r e s i a n d L u c k , 1 9 5 2 ) . 41 T e r e s i and L u c k s t u d i e d q u a n t i t a t i v e l y t h e c o m b i n a t i o n o f s e v e n s h o r t - c h a i n f a t t y a c i d s w i t h b o v i n e s e r u m a l b u m i n u s i n g e q u i l i b r i u m d i a l y s i s i n 1 9 5 2 . T h e y f o u n d t h a t b i n d i n g i n c r e a s e d a s t h e c h a i n l e n g t h i n c r e a s e d f r o m a n i o n s o f a c e t a t e t h r o u g h c a p r y l a t e a n d i n d i c a t e d t h e e x i s t a n c e o f a t l e a s t 2 c l a s s e s o f b i n d i n g s i t e s , e a c h h a v i n g a c h a r a c t e r -i s t i c a s s o c i a t i o n c o n s t a n t . H o w e v e r , t h e i r e x p e r i m e n t s w e r e l i m i t e d i n t h a t t h e i n i t i a l f a t t y a c i d c o n t e n t o f t h e b o v i n e a l b u m i n u s e d was u n k n o w n . I n s u b s e q u e n t e x p e r i m e n t s j Goodman ( 1 9 5 8 a ; 1 9 5 8 b ) a n a l y z e d t h e i n t e r a c t i o n o f human a l b u m i n w i t h 6 d i f f e r e n t l o n g - c h a i n f a t t y a c i d s b y p h a s e p a r t i t i o n a n a l y s i s . T h e r e a p p e a r d t o be 3 c l a s s e s o f b i n d i n g s i t e s o n t h e human a l b u m i n m o l e c u l e : t h e f i r s t w i t h a h i g h a s s o c i a t i o n c o n s t a n t f o r 2 m o l e s o f f a t t y a c i d , t h e s e c o n d w i t h a l o w e r a s s o c i a t i o n f o r 5 m o l e s o f f a t t y a c i d , w h i l e t h e t h i r d h a d a much l o w e r a s s o c i a t i o n c o n s t a n t f o r a b o u t 20 m o l e s o f f a t t y a c i d s . From t h e s e s t u d i e s , t h e r e a p p e a r e d t o be 2 b i n d i n g s i t e s i n t h e f i r s t c l a s s w h i c h w e r e s p e c i f i c a l l y c o n s t r u c t e d t o b i n d 16 o r 18 c a r b o n f a t t y a c i d s much more a v i d l y t h a n f a t t y a c i d s o f l o w e r c a r b o n c h a i n s ( G o o d m a n , 1 9 5 8 a ) . The s e c o n d c l a s s o f b i n d i n g s i t e s c o n t a i n e d l e s s s t r u c t u r a l s p e c i f i c i t y t h a n t h e f i r s t c l a s s . I t i s c o n c e i v a b l e t h a t t h e f i r s t c l a s s b i n d i n g s i t e s w e r e a l r e a d y o c c u p i e d a n d t h e r e f o r e w e r e n o t o b s e r v a b l e i n t h e s t u d i e s b y T e r e s i a n d L u c k ( 1 9 5 2 ) . The a n a l y s i s o f Goodman was b a s e d on t h e a s s u m p t i o n t h a t e a c h a l b u m i n m o l e c u l e h a s a d i s c r e t e number o f b i n d i n g s i t e s f o r f a t t y a c i d s a n d t h a t t h e s e s i t e s a r e i n d e p e n d e n t o f one a n o t h e r ( G o o d m a n , 1 9 5 8 a ) . I t was h y p o t h e s i z e d t h a t i n t e r a c t i o n o f a f a t t y a c i d w i t h a n y 42 one s i t e was a s i m p l e a s s o c i a t i o n - d i s s o c i a t i o n e q u i l i b r i u m w h i c h o b e y e d t h e l a w o f mass a c t i o n a n d c o u l d be d e s c r i b e d q u a n t i t a t i v e l y by an a s s o c i a t i o n c o n s t a n t ( F r e d r i c k s o n a n d G o r d o n , 1 9 5 8 ; Goodman, 1 9 5 8 a ) . The a f f i n i t y o f FFA f o r a l b u m i n d e p e n d e d o n t h e l e n g t h o f t h e h y d r o c a r b o n c h a i n a s w e l l a s t h e d e g r e e o f u n s a t u r a t i o n ( G o o d m a n , 1 9 5 8 a ) . S t u d i e s on i s o l a t e d r a t h e a r t s s h o w e d a c o n s i s t e n t r e l a t i o n s h i p b e t w e e n m y o c a r d i a l u p t a k e a n d m o l e c u l a r s t r u c t u r e ( E v a n s , 1 9 6 4 ) . I n a s e r i e s o f s a t u r a t e d f a t t y a c i d s , u p t a k e d e c r e a s e d w i t h i n c r e a s i n g c h a i n l e n g t h ( E v a n s , 1 9 6 4 ; W i l l e b r a n d , 1 9 6 4 ) , w h i c h i s c o n s i s t e n t w i t h t h e a s s o c i a t i o n c o n s t a n t s d e r i v e d by Goodman ( 1 9 5 8 a ) . As t h e c h a i n l e n g t h s i n c r e a s e d , FFA a s s o c i a t e d more t i g h t l y t o t h e a l b u m i n a n d t h u s d i d n o t d i s s o c i a t e a s r e a d i l y f o r c e l l u l a r u p t a k e . The m y o c a r d i a l e x t r a c t i o n a p p e a r e d t o be i n v e r s e l y p r o p o r t i o n a l t o t h e c h a i n l e n g t h o f t h e s a t u r a t e d f a t t y a c i d s ( E v a n s e t a l . , 1 9 6 3 b ; C a r l s t e n e t a l . , 1 9 6 1 ) . ; M o n o e n o i c a c i d s s u c h a s p a l m i t o l e i c and o l e i c a c i d s w e r e t a k e n up i n p r e f e r e n c e t o s a t u r a t e d o r d i e n o i c s p e c i e s o f e q u a l c h a i n l e n g t h ( W i l l e b r a n d , 1 9 6 4 ' ; E v a n s , 1 9 6 4 ) . The p r e f e r e n t i a l u p t a k e o f m o n o e n o i c a c i d s was a t t r i b u t e d i n p a r t t o r a p i d i n t r a c e l l u l a r u t i l i z a t i o n s i n c e 14 i n s t u d i e s w i t h C - l a b e l e d f a t t y a c i d s , o l e i c a c i d was o x i d i z e d more r e a d i l y t h a n e i t h e r s t e a r i c o r l i n o l e i c a c i d ( E v a n s , 1 9 6 4 ) . M o d i f i c a t i o n s i n t h e s t r u c t u r e o f FFA a l t e r e d t h e s t r e n g t h o f b i n d i n g t o b o v i n e s e r u m a l b u m i n (BSA) ( S p e c t o r , J o h n s a n d F l e t c h e r 1 9 6 9 ) . B i n d i n g o f t h e FFA was g r e a t l y a f f e c t e d i f t h e c a r b o x y l i c g r o u p was m o d i f i e d o r r e m o v e d ( S p e c t o r e t a l . , 1 9 6 9 ) . I t w o u l d a p p e a r t h a t f a t t y a c i d ' b i n d i n g t o a l b u m i n was 4 3 d e p e n d e n t o n 1) e l e c t r o s t a t i c a t t r a c t i o n o f t h e c a r b o x y l i c g r o u p o f t h e f r e e f a t t y a c i d t o t h e p r o t e i n c a t i o n s i t e , 2) h y d r o p h o b i c i n t e r -a c t i o n s b e t w e e n t h e n o n - p o l a r h y d r o c a r b o n c h a i n a n d t h e n o n - p o l a r s i d e c h a i n s o f t h e a l b u m i n ( S p e c t o r e t a l . , 1 9 6 9 ; Goodman, 1 9 5 8 a ) . The e f f e c t o f c h a i n l e n g t h a n d u n s a t u r a t i o n on t h e c e l l u l a r t r a n s p o r t o f i n d i v i d u a l f a t t y a c i d s was a t t r i b u t e d t o d i f f e r e n c e s i n s o l u b i l i t y i n a q u e o u s m e d i a , s t r e n g t h o f b i n d i n g t o a l b u m i n , a f f i n i t y t o t i s s u e b i n d i n g s i t e s , a n d r a t e o f i n t r a c e l l u l a r u t i l i z a t i o n ( E v a n s , 1 9 6 4 ) . c ) The U t i l i z a t i o n o f I n t r a c e l l u l a r F r e e F a t t y A c i d The f a t e o f i n c o r p o r a t e d f a t t y a c i d s was d e t e r m i n e d i n E h r l i c h c e l l s l o a d e d w i t h r a d i o a c t i v e FFA w h i c h w e r e t h e n r e i n c u b a t e d i n a / x 14 s e c o n d medium ( S p e c t o r e t a l . , 1 9 6 5 a ) . A l a r g e p o r t i o n o f t h e C-p a l m i t a t e i n i t i a l l y i n c o r p o r a t e d i n t o t h e c e l l was s u b s e q u e n t l y m e t a b o l i z e d d u r i n g r e i n c u b a t i o n a n d t h e l a b e l was r e c o v e r e d a l m o s t q u a n t i t a t i v e l y a s c a r b o n d i o x i d e a n d l i p i d e s t e r s ( S p e c t o r e t a l . , 1 9 6 5 a ; S p e c t o r , 1 9 6 8 ) . A t l o w c e l l FFA c o n c e n t r a t i o n s , t h e r a t e o f 14 p r o d u c t i o n was p r o p o r t i o n a l t o t h e i n i t i a l a m o u n t o f r a d i o a c t i v e FFA i n t h e c e l l . H o w e v e r , a s t h e c e l l u l a r FFA l e v e l i n c r e a s e d , t h e s y s t e m a p p e a r e d t o a p p r o a c h s a t u r a t i o n . Two f a c t o r s a p p e a r e d t o r e g u l a t e FFA u t i l i z a t i o n : 1) FFA c o n t e n t o f t h e c e l l 2) t h e t u r n - o v e r r a t e , o f t h e c e l l u l a r FFA p o o l ( E v a n s , 1 9 6 4 ) . The e x i s t a n c e o f two p o o l s o f i n t r a c e l l u l a r f r e e f a t t y a c i d s was shown by S h o h e t e t a l . i n 1 9 6 8 u s i n g human e r y t h r o c y t e s . T h e r e a p p e a r e d t o be a s u p e r f i c i a l membrane p o o l t o w h i c h t h e FFA was r e v e r s i b l y b o u n d a s w e l l a s a 1 d e e p e r m e m b r a n e p o o l w i t h i r r e v e r s i b l e 44 b i n d i n g . The p a s s a g e o f FFA i n t o t h e s u p e r f i c i a l membrane p o o l was e n e r g y - i n d e p e n d e n t w h i l e p a s s a g e i n t o t h e d e e p e r membrane p o o l r e q u i r e d m e t a b o l i c e n e r g y ( S p e c t o r , 1 9 7 1 ) . B o t h o f t h e s e p o o l s w e r e c a l c u l a t e d t o be o f e q u a l s i z e a l t h o u g h u p t a k e o f FFA i n t o t h e s u p e r f i c i a l membrane p o o l was t w e n t y t i m e s f a s t e r t h a n movement i n t o t h e ' d e e p e r ' membrane p o o l ( S p e c t o r , 1 9 7 1 ) . O x i d a t i o n o f f a t t y a c i d s was f o u n d t o o c c u r i n t h e m i t o -c h o n d r i a , i n w h i c h m e t a b o l i s m o f medium c h a i n f a t t y a c i d s d i f f e r e d f r o m t h a t o f l o n g c h a i n f a t t y a c i d s . Medium c h a i n f a t t y a c i d s s u c h as o c t a n o i c a c i d c a n p e n e t r a t e t h e i n n e r m i t o c h o n d r i a l membrane w h e r e a s l o n g c h a i n f a t t y a c i d s r e q u i r e d an i n i t i a l a c t i v a t i o n p r i o r t o p a r t i -c i p a t i o n i n a n y m e t a b o l i c p a t h w a y s ( S p e c t o r , 1 9 7 1 ) . i d ) C a r n i t i n e ( B e t a - h y d r o x y g a m m a - t r i m e t h y l ammonium b u t y r a t e ) A l t h o u g h t h e t r a n s f e r o f f a t t y a c i d b e t w e e n t h e p l a s m a a n d t h e b i n d i n g s i t e s on t h e m y o c a r d i a l c e l l membranes i s n o t e n e r g y -d e p e n d e n t ; l o n g - c h a i n f a t t y a c i d s m u s t u n d e r g o a c t i v a t i o n f r o m t h e s e s i t e s p r i o r t o a c t i v e c e l l u l a r m e t a b o l i s m ( E v a n s , 1 9 6 4 ) . The p r e s e n c e o f c a r n i t i n e was f o u n d t o be e s s e n t i a l f o r t h e o x i d a t i o n o f l o n g c h a i n FFA by h e a r t m i t o c h o n d r i a ( B o d e and K l i n g e n b e r g , 1 9 6 4 ) . H i g h c a r n i t i n e c o n c e n t r a t i o n s w e r e f o u n d i n t i s s u e s w h i c h w e r e d e p e n d e n t on f a t t y a c i d s a s t h e m a j o r f u e l f o r r e s p i r a t i o n , p r i m a r i l y t h e h e a r t a n d t h e s k e l e t a l m u s c l e s ( M a r q u i s and F r i t z , 1 9 5 4 ) . The a c t i v i t y o f c a r n i t i n e was f o u n d t o be d e p e n d e n t on s t r u c t u r a l c o m p o n e n t s and c o f a c t o r s o f t h e c e l l a n d d i r e c t e d t o w a r d s t h e f a t t y a c i d o x i d a s e s y s t e m ( E v a n s , 1 9 6 4 ) . The i n d e p e n d e n t s t u d i e s o f F r i t z 45 a n d Yue ( 1 9 6 3 ) a n d B r e m e r . ( 1 9 6 3 ) d e m o n s t r a t e d t h e c a t a l y t i c r o l e o f c a r n i t i n e a s a c a r r i e r o f l o n g c h a i n f a t t y a c i d s f r o m t h e e x t r a m i t o -c h o n d r i a l a c y l - c o e n z y m e A p o o l t o t h e i n t r a c e l l u l a r f a t t y a c i d o x i d a s e s y s t e m . T h i s was t h o u g h t t o be m e d i a t e d by c a r n i t i n e a c y l - t r a n s f e r a s e , w h i c h t r a n s f e r r e d a c y l - C o A a s a p e r m e a b l e c a r n i t i n e i n t e r m e d i a t e a c r o s s t h e i n n e r m i t o c h o n d r i a l membrane ( F r i t z a n d Y u e , 1 9 6 4 ) . W i t h i n t h e m i t o -c h o n d r i a l m a t r i x , a c y l - c a r n i t i n e was c o n v e r t e d b a c k t o a c y l - C o A , t h u s c o n f i r m i n g t h e s h u t t l e c a p a c i t y o f c a r n i t i n e f o r t h e a c y l m o i e t y a c r o s s t h e i n n e r m i t o c h o n d r i a l membrane ( B r e m e r a n d W o j t c z a k , 1 9 7 2 ; H o p p e l a n d T o m e c , 1 9 7 2 ) . T h u s , c a r n i t i n e p l a y s a c r u c i a l r o l e i n t h e t r a n s p o r t o f a c t i v a t e d l o n g c h a i n f a t t y a c y l g r o u p s f r o m e x t r a m i t o c h o n d r i a l s i t e s o f a c t i v a t i o n t o s i t e s o f b e t a o x i d a t i o n w i t h i n t h e i n n e r membrane m a t r i x o f t h e m i t o c h o n d r i a . e ) O x i d a t i o n o f F a t t y A c i d s O x i d a t i v e d e g r a d a t i o n o f f a t t y a c i d s i s a u n i v e r s a l b i o c h e m i c a l c a p a c i t y among l i v i n g o r g a n i s m s ( C h a p m a n , 1 9 6 9 ) . I n m a m m a l s , s u c h o x i d a t i o n o c c u r s i n t h e l i v e r , k i d n e y s , a n d h e a r t . I n t r a c e l 1 u l a r l y , f a t t y a c i d o x i d a t i o n o c c u r s p r i n c i p a l l y i n t h e m i t o c h o n d r i a . O x i d a t i o n o f f a t t y a c i d s t o a c e t y l - C o A i n v o l v e s t h r e e enzyme s y s t e m s ; t h e a c y l - C o A s y n t h e t a s e s ; t h e c a r n i t i n e a c y l t r a n s f e r a s e ; a s w e l l a s e n z y m e s o f t h e b e t a - o x i d a t i o n s y s t e m ( S p e c t o r , 1 9 7 1 ) . A l l o f t h e s e enzyme s y s t e m s a r e l o c a t e d i n t h e o u t e r membrane s u b f r a c t i o n o f i s o l a t e d m i t o c h o n d r i a ( S p e c t o r , 1 9 6 8 ) . B e t a - o x i d a t i o n c a t a l y s e s t h e s t e p w i s e c o n v e r s i o n o f l o n g c h a i n a c y l - C o A ' s t o a number o f a c e t y l - C o A m o i e t i e s ( G i l b e r t s o h , 1 9 7 7 ) . A l t h o u g h a l p h a , b e t a , a n d o m e g a - o x i d a t i o n o f l o n g c h a i n f a t t y a c i d s a r e known t o 46 o c c u r , b e t a o x i d a t i o n i s t h e o n l y one o f a n y s i g n i f i c a n c e . ( i ) B e t a O x i d a t i o n I n b e t a o x i d a t i o n , t h e p a r e n t f a t t y a c i d i s a c t i v a t e d by r e a c t i o n w i t h C o e n z y m e - A t o f o r m f a t t y a c y l - S C o A , w h i c h i s s u b s e q u e n t l y o x i d i z e d t o an a l p h a - b e t a - u n s a t u r a t e d c o m p o u n d . I t i s t h e n h y d r a t e d , f u r t h e r o x i d i z e d t o t h e b e t a - k e t o d e r i v a t i v e , a n d f i n a l l y s u b j e c t e d t o a t h i o l y t i c c l e v a g e y i e l d i n g a c e t y l - S CoA a n d t h e f a t t y a c y l - S CoA c o n t a i n i n g 2 l e s s c a r b o n atoms ( S a c k h e i m 3 a n d S c h u l t z , 1 9 7 7 ) . T h i s same s e r i e s o f r e a c t i o n s i s r e p e a t e d , r e d u c i n g t h e c a r b o n c h a i n by 2 c a r b o n s s e a c h t i m e . The b y - p r o d u c t s as w e l l as t h e e n d p r o d u c t o f b e t a - o x i d a t i o n o f an e v e n c h a i n f a t t y a c i d a r e a c e t y l CoA m o i e t i e s w h i c h e n t e r t h e K r e b s o r T r i c a r b o x y l i c a c i d c y c l e . The f i n a l p r o d u c t s o f t h e K r e b s c y c l e a r e c a r b o n d i o x i d e , w a t e r , a n d e n e r g y (ATP) ( S a c k h e i m a n d S c h u l t z , 1 9 7 7 ) . F a t t y a c i d s w h i c h c o n t a i n an o d d number o f c a r b o n atoms a r e m e t a b o l i z e d i n t h e same way w i t h t h e e x c e p t i o n t h a t t h e f i n a l p r o d u c t s a r e a c e t y l CoA a n d p r o p i o n y l CoA ( S a c k h e i m a n d S c h u l t z , 1 9 7 7 ) . T h r o u g h a s e r i e s o f s t e p s , p r o p i o n y l CoA i s c h a n g e d t o s u c c i n y l C o A , w h i c h e n t e r s t h e K r e b s c y c l e , as does t h e a c e t y l CoA. U n s a t u r a t e d f a t t y a c i d s a r e m e t a b o l i z e d s l o w l y as t h e y m u s t be r e d u c e d by d e h y d r o g e n a s e s f i r s t . T h e y a r e t h e n o x i d i z e d i n t h e same m a n n e r as. t h e s a t u r a t e d f a t t y a c i d s . ( i i ) A l p h a O x i d a t i o n Enzymes f o r a l p h a o x i d a t i o n h a v e b e e n r e p o r t e d i n t h e l i v e r a n d b r a i n m i c r o s o m e s ( C h a p m a n , 1 9 6 9 ; L e v i s a n d M e a d , 1 9 6 4 ) . A l p h a o x i d a t i o n i s n o t a m a j o r p a t h w a y f o r f a t t y a c i d c a t a b o l i s m b u t i s e s s e n t i a l f o r 0 CH 2-CH=CH-C-S-CoA trans-a:,g- u n s a t u r a t e d f a t t y a c i d a c y l CoA-dehydro-genase c FADH. FAD - CH 2-CH 2-CH 2-C-S-CoA enoyl-CoA h y d r a t a s e a c y l CoA-dehydrogenase OH 0 i 11 GH 2=CH-CH 2-C-S-CoA 3 - h y d r o x y f a t t y a c i d NAD NADH 0 ii g - h y d r o x y a c y l CoA dehydrogenase CH 2-C-CH 2-C-S-CoA a c t i v e f a t t y a c i d t h i o k i n a s e CoASH 5 s - C AMP +. p p i ATP CH 2-CH 2-CH 2-C-OH f a t t y a c i d g - k e t o f a t t y a c i d CoASH CH 2-C-S-CoA a c t i v e f a t t y a c i d o f two l e s s c a r b o n atoms g - k e t o t h i o l a s e CH 3-C-S-eoA a c e t y l CoA O x i d a t i o n o f a F a t t y A c i d CITRIC ACID CYCLE C o 2 + H 20 * ATP F i g u r e 1: S c h e m a t i c O u t l i n e o f t h e B e t a O x i d a t i o n C y c l e o f F a t t y A c i d s w i t h an Even Number o f Carbon Atoms (Sackheim arid S e h u l t z , 1977.) 4 8 d e g r a d a t i o n o f c e r t a i n b r a n c h e d c h a i n f a t t y a c i d s ( A n t h o n y and L a n d a u , 1 9 6 8 ) . D u r i n g a l p h a o x i d a t i o n , an h y d r o x y l g r o u p i s i n s e r t e d on t h e s e c o n d o r a l p h a c a r b o n o f t h e f a t t y a c i d , f o r m i n g a n a l p h a - h y d r o x y a c i d . T h i s a l p h a - h y d r o x y a c i d f o r m s an i n t e r m e d i a t e a l p h a - k e t o a c i d , a n d f r o m s u b s e q u e n t o x i d a t i v e d e c a r b o x y l a t i o n s , y i e l d s an o d d - n u m b e r e d l o n g c h a i n f a t t y a c i d ( C h a p m a n , ! 9 6 9 ) . ( i i i ) O m e g a - O x i d a t i o n Omega o x i d a t i o n may a c c o m p a n y b e t a - o x i d a t i o n a n d i n c l u d e s ' an o x i d a t i v e a t t a c k on t h e t e r m i n a l c a r b o n o f t h e h y d r o c a r b o n c h a i n . The 2 - s t e p p a t h w a y i n c l u d e s f o r m a t i o n o f a n o m e g a - h y d r o x y f a t t y a c i d . O x i d a t i o n o f t h i s h y d r o x y - a c i d r e q u i r e s c o f a c t o r s a n d e n z y m e s (Den e t a l , 1 9 5 9 ) . Once t h e d i c a r b o x y l i c a c i d i s f o r m e d , b e t a o x i d a t i o n c a n o c c u r a t b o t h ' p o s i t i o n s . F o r m a t i o n o f t h e d i c a r b o x y l i c a c i d i s m o s t p r o m i n e n t i n a c i d s c o n t a i n i n g 8 - 1 2 c a r b o n s ( C h a p m a n , 1 9 6 9 ) . O m e g a - o x i d a t i o n i s n o t an i m p o r t a n t p a t h w a y f o r f a t t y a c i d d e g r a d a t i o n u n d e r n o r m a l c i r c u m -s t a n c e s . f ) M y o c a r d i a l M e t a b o l i s m i n A c u t e M y o c a r d i a l . I n f a r c t i o n M y o c a r d i a l i s c h e m i a i s r e f l e c t e d by an a l t e r a t i o n i n m e t a b o l i s m , d e p e n d i n g on t h e s e v e r i t y o f o x y g e n d e p r i v a t i o n . I n s t u d i e s o f r a t h e a r t s u n d e r g o i n g i n c r e a s i n g d e g r e e s o f o x y g e n d e p r i v a t i o n , t h e r e was a p r o g r e s s i v e d e c r e a s e i n t h e r a t e o f FFA u p t a k e ( G i l b e r t s o n , 1 9 7 7 ) . I n a d d i t i o n , t h e m e t a b o l i c f a t e o f t h e f a t t y a c i d s w h i c h w e r e t a k e n up by t h e h e a r t a l s o v a r i e d w i t h t h e a v a i l a b i l i t y o f o x y g e n . I n i n f a r c t s , t h e f a t t y a c i d s . w e r e n o t o x i d i z e d f o r e n e r g y , b u t a c c u m u l a t e d w i t h i n t h e 49 m y o c a r d i a l c e l l s as f a t d r o p l e t s ( B i l h e i m e r e t a l , 1 9 7 8 ) . The b a s i s o f u s i n g r a d i o i o d i n a t e d f a t t y a c i d s f o r m y o c a r d i a l s c a n n i n g i s b a s e d on t h e d e c r e a s e d u p t a k e i n m y o c a r d i a l c e l l s d e p r i v e d o f o x y g e n . T h i s d e c r e a s e d u p t a k e c a n be v i s u a l i z e d on a m y o c a r d i a l s c a n a s a 1 c o l d s p o t ' . 5 . I o d i n e - 1 2 3 I o d i n e - 1 2 3 f u l f i l s t h e c r i t e r i a o f t h e i d e a l r a d i o n u c l i d e f o r i n s i t u a n d i n v i v o d i a g n o s t i c p r o c e d u r e s . 1 - 1 2 3 e m i t s 159 KeV gamma r a y s i n 84% a b u n d a n c e ( P o e , 1 9 7 5 ; M y e r s , 1 9 6 6 ) . T h i s e n e r g y i s w i t h i n t h e i d e a l e n e r g y r a n g e a n d c a n be e f f i c i e n t l y c o l l i m a t e d w i t h t h e c a m e r a s p r e s e n t l y a v a i l a b l e . The s h o r t 1 3 . 0 h o u r s h a l f - 1 i f e i s d e s i r a b l e i;n t h a t l a r g e d o s e s c a n be a d m i n i s t e r e d a n d s e r i a l a d m i n i s t r a t i o n s c a n be made w i t h i n s h o r t t i m e i n t e r v a l s . I o d i n e - 1 2 3 d e c a y s by e l e c t r o n c a p t u r e and t h e l a c k o f a n y a l p h a o r b e t a e m i s s i o n s r e d u c e s t h e r a d i a t i o n e x p o s u r e t o t h e p a t i e n t . I o d i n e - 1 2 3 p r o v i d e s i m p r o v e d c o u n t i n g s t a t i s t i c s o v e r t h e o t h e r i s o t o p e s o f i o d i n e a v a i l a b l e ( P o e , 1 9 7 5 ) . I o d i n e - 1 2 3 c a n be p r o d u c e d by v a r i o u s d i r e c t o r i n d i r e c t m e t h o d s . 123 The i n d i r e c t m e t h o d s i n v o l v e t h e i n i t i a l p r o d u c t i o n o f X e , w h i c h t h e n 123 d e c a y s t o I . The a d v a n t a g e o f t h e i n d i r e c t m e t h o d o f p r o d u c t i o n i s t h e l a c k o f r a d i o i o d i d e c o n t a m i n a n t s ( S o d d , 1 9 7 5 ) . By f i r s t p r o d u c i n g x e n o n - 1 2 3 , t h e r e i s no p r o b l e m i n t h e s e p a r a t i o n o f t h e x e n o n - 1 2 3 f r o m t h e 123 123 i o d i n e - 1 2 3 . The d e c a y o f Xe r e s u l t s i n m o n o a t o m i c I a t o m s w h i c h a r e c h e m i c a l l y r e a c t i v e and c a n be u t i l i z e d f o r d i r e c t l a b e l i n g r e a c t i o n s i n t h e f u t u r e ( S o d d , 1 9 7 5 ) . 50 T h e r e h a v e b e e n many m e t h o d s r e p o r t e d f o r t h e p r o d u c t i o n o f 123 127 123 X e . The I ( p , 5 n ) Xe r e a c t i o n i s one o f t h e m e t h o d s o f c h o i c e . The s t a r t i n g m a t e r i a l i s r e a d i l y a v a i l a b l e a n d i n e x p e n s i v e . The d i s a d v a n t a g e o f t h i s r e a c t i o n i s t h a t o n l y a l i m i t e d number o f a c c e l e r a t o r s a r e c a p a b l e o f p r o d u c i n g p h o t o n s w i t h . e n e r g i e s a r o u n d 50 M e V . The s p a l l a t i o n p r o c e s s i s l i m i t e d i n t h a t i m p u r i t i e s i n t h e f o r m o f n e i g h b o r i n g r a d i o i s o t o p e s and r a d i o e l e m e n t s a r e p r o d u c e d i n q u a n t i t i e s c o m p a r a b l e t o t h e d e s i r e d r a d i o i s o t o p e . I o d i n e - 1 2 3 c a n be p r o d u c e d d i r e c t l y f r o m b o m b a r d m e n t o f e n r i c h e T e l l u r i u m t a r g e t s . D i r e c t m e t h o d s o f p r o d u c t i o n a r e l i m i t e d by t h e c o s t a s w e l l a s t h e p u r i t y o f t h e i s o t o p i c e n r i c h m e n t o f t h e T e l l u r i u m t a r g e t s c o m m e r c i a l l y a v a i l a b l e . I n a d d i t i o n , t h e r e i s a l w a y s some c o n t a m i n a t i o n by I o d i n e - 1 2 4 , w h i c h i s i m p o s s i b l e t o s e p a r a t e f r o m I o d i n e -I t c a n be s e e n t h a t I o d i n e - 1 2 3 h a s g r e a t p o t e n t i a l i n n u c l e a r m e d i c i n e . P r o b l e m s w i t h c o n t a m i n a n t s may be r e d u c e d o r e l i m i n a t e d by r ' a l t e r a t i o n s i n t h e p r o d u c t i o n m e t h o d s . H o w e v e r , b e c a u s e o f t h e s h o r t h a l f - l i f e a n d t h e n e c e s s i t y o f d i r e c t c y c l o t r o n p r o d u c t i o n , i t s r o u t i n e a c c e p t a n c e i n n u c l e a r m e d i c i n e w i l l be l i m i t e d u n t i l more c y c l o t r o n s a r e made a v a i l a b l e f o r i t s p r o d u c t i o n . 6 . R a d i o i o d i n a t e d F a t t y A c i d s As d i s c u s s e d , f a t t y a c i d s a r e known t o be a m a j o r s o u r c e o f f u e l f o r m y o c a r d i a l m e t a b o l i s m , a n d a r e d i s t r i b u t e d a c c o r d i n g t o b l o o d f l o w t o o x y g e n a t e d , f u n c t i o n a l m y o c a r d i a l c e l l s . I n a s e a r l y a s 1 9 6 2 , 51 E v a n s e t a l , w e r e i n v e s t i g a t i n g t h e u s e o f r a d i o i o d i n a t e d o l e i c a c i d f o r p h o t o s c a n s o f t h e h e a r t . The r a d i o i o d i n a t e d o l e i c a c i d was b o u n d t o a l b u m i n a n d i n j e c t e d i n t o d o g s i n w h i c h m y o c a r d i a l i n f a r c t i o n s had b e e n p r o d u c e d . I n t h e s e e a r l y s c a n s , d e f i n i t i o n b e t w e e n n o r m a l m y o c a r d i u m a n d d e g r e e s o f i n f a r c t i o n was o n l y m a r g i n a l . I n a d d i t i o n , f r e e r a d i o i o d i d e c o n c e n t r a t e d i n t h e g a s t r i c m u c o s a , t h u s o b s c u r i n g t h e l o w e r b o r d e r o f t h e h e a r t . R e s u l t s i n human s u b j e c t s w i t h m y o c a r d i a l i n f a r c t i o n s s h o w e d s i m i l a r d i s t r i b u t i o n t o t h e c a n i n e s t u d i e s . The l i m i t e d s u c c e s s o f t h e s e e a r l y s c a n s w e r e a t t r i b u t e d i n p a r t t o t h e l o w s p e c i f i c - a c t i v i t y l a b e l p r o d u c e d . F u r t h e r m o r e , t h e i m a g i n g p r o p e r t i e s o f I o d i n e - 1 3 1 a s w e l l a s t h e r a d i a t i o n e x p o s u r e t o t h e p a t i e n t s w e r e u n f a v o r a b l e . S u b s e q u e n t c l i n i c a l t r i a l s c a r r i e d o u t by G u n t o n e t a l . 131 ( 1 9 6 5 ) d e m o n s t r a t e d s u f f i c i e n t i n c o r p o r a t i o n o f I - o l e i c a c i d f o r m y o c a r d i a l s c a n s i n w h i c h d e f i n i t e a r e a s o f d e c r e a s e d r a d i o a c t i v i t y c o r r e s p o n d e d t o t h e l o c a t i o n o f t h e - i n f a r c t i o n . The r a d i o i o d i n a t e d f a t t y a c i d was f o u n d t o be i n c o r p o r a t e d i n t o t i s s u e t r i g l y c e r i d e s a n d p h o s p h o l i p i d s . T h i s i n c o r p o r a t i o n was e n h a n c e d by t h e s i m u l t a n e o u s a d m i n i s t r a t i o n o f g l u c o s e a n d i n s u l i n . H o w e v e r , t h e s c a n s o b t a i n e d w e r e n o t d e f i n i t i v e due t o r a d i o a c t i v i t y p r e s e n t i n t h e t h o r a c i c s k e l e t a l m u s c l e , l u n g s , a n d f u n d u s o f t h e s t o m a c h . The q u a l i t y o f t h e s c a n s was p o o r a n d s c a n s o f d i a g n o s t i c q u a l i t y w e r e o b t a i n e d i n o n l y 50% o f t h e s t u d i e s ( G u n t o n ^ e t a l . , 1 9 6 5 ) . U n t i l 1 9 7 3 , o n l y 1-131 l a b e l e d o l e i c , l i n o l e i c , a n d l i n o l e n i c a c i d s h a d b e e n i n v e s t i g a t e d . A l t h o u g h t h e s y n t h e s i s o f h i g h - s p e c i f i c 52 a c t i v i t y c o m p o u n d s h a d b e e n a c h i e v e d , t h e . i m a g i n g p r o p e r t i e s o f I o d i n e - 1 3 1 w e r e s t i l l s u b o p t i m a l f o r t h e gamma c a m e r a s a v a i l a b l e ( A n g h i l e r i , 1 9 6 5 ; Poe e t a l . , 1 9 7 3 ) . T h u s , new r a d i o i s o t o p e s w e r e s o u g h t t o l a b e l l o n g c h a i n f a t t y a c i d s . Due t o t h e p r o v e n u s e f u l n e s s o f T e c h n e t i u m - 9 9 m a s a r a d i o -n u c l i d e , an a t t e m p t was made t o l a b e l l o n g c h a i n f a t t y a c i d s b y B o n t e 99m e t a l . ( 1 9 7 3 ) . T c - o l e i c a c i d was i n j e c t e d i n t r a v e n o u s l y i n t o d o g s w i t h a r t i f i c i a l l y i n d u c e d i s c h e m i c a r e a s . The r e s u l t a n t s c a n s , h o w e v e r , w e r e o f p o o r r e s o l u t i o n a n d s h o w e d , h i g h b a c k g r o u n d a c t i v i t y . C a r b o n - 1 1 a n d F l u o r i n e - 1 8 w e r e . a l s o u s e d t o l a b e l v a r i o u s c a r b o x y l i c a c i d s by Poe e t a l . ( 1 9 7 3 ) . The m y o c a r d i a l e x t r a c t i o n 11 18 18 c a p a c i t y f o r C - o l e a t e , F - h e x a n o a t e , a n d F - t e t r a d e c a n o a t e w e r e c o m p a r e d ( P o e e t a l . , 1 9 7 3 ) . The ^ C - o l e a t e was a l m o s t i d e n t i c a l i n i t s e x t r a c t i o n p a t t e r n by t h e m y o c a r d i u m t o K - 4 3 w h i l e t h e f l u o r i n e - 1 8 a n a l o g s d e m o n s t r a t e d a b o u t o n e - h a l f o f t h e e x t r a c t i o n c a p a c i t y o f K - 4 3 . I t i s d o u b t f u l w h e t h e r t h e s e r a d i o n u c l i d e s w i l l be r e a d i l y a v a i l a b l e a s o n - s i t e f a c i l i t i e s a r e e s s e n t i a l f o r t h e i r p r o d u c t i o n . W i t h t h e p r o d u c t i o n o f I o d i n e - 1 2 3 , a r a d i o n u c l i d e w i t h a l m o s t i d e a l i m a g i n g p r o p e r t i e s , a t t e n t i o n was a g a i n f o c u s e d o n r a d i o i o d i n a t i o n o f f a t t y a c i d s . . P r e v i o u s t o 1 9 7 4 , t h e m a j o r i t y o f t h e m y o c a r d i a l s c a n s 131 w e r e done u s i n g I - o l e i c a c i d . T h i s was p r o b a b l y due t o t h e a v a i l a b i l i t y , t h e l o w c o s t , a n d t h e e a s e o f r a d i o i o d i n a t i o n a c r o s s t h e d o u b l e b o n d . H o w e v e r , by 1 9 7 4 , i t was r e c o g n i z e d by Poe e t a l . t h a t f a t t y a c i d s r a d i o i o d i n a t e d a c r o s s a d o u b l e b o n d e x h i b i t e d d i f f e r e n t b i o l o g i c a l b e h a v i o r t o t h e i r n o n - r a d i o i o d i n a t e d c o u n t e r p a r t s . The r a d i o i o d i n a t i o n 53 a p p e a r e d t o a l t e r t h e s h a p e o f t h e . f a t t y a c i d m o l e c u l e a n d ' t h u s a f f e c t t h e m y o c a r d i a l e x t r a c t i o n ( P o e , e t - a l , , 1 9 7 4 ) . T h i s h y p o t h e s i s was s u b s e q u e n t l y c o n f i r m e d by t h e s t u d i e s o f B e i e r w a l t e s e t a l . ( 1 9 7 5 ) . C o n s i d e r a t i o n o f t h i s p r o b l e m .l:ed t o t h e e v a l u a t i o n o f 123 1 6 - I - h e x a d e c e n o i c a c i d f o r m y o c a r d i a l s c a n n i n g ( R o b i n s o n e t a l . , 1 9 7 4 ; Poe e t a l . , 1 9 7 4 ) . In 16 - i o d o h e x a d e c e n o i c a c i d , t h e 1 - 1 2 3 l a b e l was on t h e omega c a r b o n , t h e r e b y h a v i n g m i n i m a l s t e a r i c i n t e r f e r e n c e and n o t a l t e r i n g t h e s h a p e o f t h e m o l e c u l e . P r e l i m i n a r y s t u d i e s i n d i c a t e d t h a t t e r m i n a l r a d i o i o d i n a t e d compounds w e r e m e t a b o l i z e d i n a f a s h i o n s i m i l a r t o t h a t o f t h e p a r e n t compound ( P o e e t a l . , 1 9 7 4 ) . From d a t a o n i n t r a c o r o n a r y a d m i n i s t r a t i o n , t h e e x t r a c t i o n a n d b l o o d c l e a r a n c e o f 1 6 - i o d o h e x a d e c e n o i c a c i d was f o u n d t o a p p r o a c h t h a t o f P o t a s s i u m - 4 3 ( R o b i n s o n e t a l . , 1 9 7 4 ) . By 1 9 7 5 , R o b i n s o n a n d Lee h a d d e v e l o p e d a m e t h o d f o r t h e p r e p a r a t i o n o f h i g h s p e c i f i c a c t i v i t y t e r m i n a l l y r a d i o i o d i n a t e d f a t t y a c i d s . T h i s l a b e l i n g p r o c e d u r e was o f s h o r t e n o u g h d u r a t i o n t o p e r m i t t h e u s a g e o f I o d i n e - 1 2 3 . The m y o c a r d i a l u p t a k e o f 6 - i o d o h e x a n o i c a n d 1 1 - i o d o u n d e c a n o i c a c i d s Were i n f e r i o r t o t h a t o f 1 6 - i o d o h e x a d e c e n o i c a c i d R o b i n s o n a n d L e e , 1 9 7 5 ) . I n a d d i t i o n , h y d r o l y t i c l i b e r a t i o n o f r a d i o -i o d i d e f r o m t e r m i n a l l y l a b e l e d f a t t y a c i d s was f o u n d t o be i n v e r s e l y r e l a t e d t o c a r b o n c h a i n l e n g t h . I t was p o s t u l a t e d t h a t i n t e r m i n a l l y l a b e l e d f a t t y a c i d s , t h e i o d i n e a t o m m a i n t a i n e d a c o n f i g u r a t i o n s i m i l a r t o t h e m e t h y l g r o u p . T h u s , t h e r e s u l t a n t m o l e c u l e . b e h a v e d s i m i l a r l y t o t t h e n e x t h i g h e r c a r b o n f a t t y a c i d ( P o e e t a l . , 1 9 7 5 ) . T h i s a p p e a r s q u i t e p r o b a b l e due t o t h e s i m i l a r a t o m i c r a d i u s o f t h e i o d i d e 54 a t o m t o a m e t h y l g r o u p ( K o r o l k o v a s , 1 9 7 0 ) . The h i g h m y o c a r d i a l e x t r a c t i o n o f t h e t e r m i n a l r a d i o i o d i n a t e d x a r b o x y l i c a c i d s c o u l d be a t t r i b u t e d t o t h e i r s t r u c t u r a l r e s e m b l a n c e t o t h e t r u e ' p h y s i o l o g i c ' u n s a t u r a t e d f a t t y a c i d s ( P o e e t a l . , 1 9 7 5 ; 1 9 7 6 ) . E c k e l m a n e t a l . ( 1 9 7 5 ) a t t e m p t e d t o s y n t h e s i z e f a t t y a c i d s and l o n g c h a i n h y d r o c a r b o n a n a l o g s w i t h s t r o n g c h e l a t i n g g r o u p s t o t r a n s p o r t m e t a l l i c i s o t o p e s t o t h e m y o c a r d i u m . H o w e v e r , i n c o n s i s t e n t p r o d u c t i o n a n d v a r i a b l e b i o l o g i c a l b e h a v i o r r e n d e r e d t h e s e compounds t o be o f l i m i t e d u s e . A d d i t i o n a l e x p e r i m e n t s were<done on t h e b i o l o g i c a l b e h a v i o r o f 1 6 - i o d o h e x a d e c e n o J c " a c i d by Poe e t a l . ( 1 9 7 6 b , 1 9 7 7 ) . A n a l y s i s o f c a n i n e b l o o d s a m p l e s 10 m i n u t e s a f t e r i n j e c t i o n r e v e a l e d o v e r 75% o f t h e a c t i v i t y p r e s e n t was f r e e i o d i d e - ! 3 1 ( P o e e t a l . , 1 9 7 6 b ) . The f r e e i o d i d e - 1 3 1 was a t t r i b u t e d t o t h e c o m p l e t e m e t a b o l i s m o f t h e o r i g i n a l f a t t y a c i d m o l e c u l e ; w i t h h y d r o l y s i s o f i o d o a c e t a t e , t h e . : e n d p r o d u c t o f b e t a - o x i d a t i o n ( P o e e t a l . , 1 9 7 6 b , R o b i n s o n a n d L e e , 1 9 7 5 ) . The b o u n d c o m p o n e n t i n t h e b l o o d r e p r e s e n t e d a m i x t u r e o f r e s i d u a l l a b e l e d h e x a d e c e n o i c a c i d , i o d i n a t e d b r e a k d o w n p r o d u c t s , a n d r e l e a s e d i o d i n e b o u n d t o p l a s m a p r o t e i n s ( P o e e t a l . , 1 9 7 6 b ) - I n t h e h e a r t , 1 6 -i o d o h e x a d e c e n o i c a c i d was f o u n d t o h a v e a m y o c a r d i a l c l e a r a n c e h a l f - t i m e o f 20 m i n u t e s . The d i s t r i b u t i o n p a t t e r n s f o u n d w e r e s i m i l a r t o t h a t o f K - 4 3 i n a n i m a l s w i t h a c u t e o r c h r o n i c i n f a r c t i o n s ( P o e e t a l , 1 9 7 6 b ) . Good q u a l i t y i m a g e s w e r e a t t a i n a b l e w i t h i n 2 - 3 m i n u t e s . I n r e c e n t s t u d i e s , M a c h u l l a e t a l . ( 1 9 7 8 ) e v a l u a t e d f a t t y a c i d s l a b e l e d w i t h C a r b o n - 1 1 , e h l o r i . n e - 3 4 m , B r o m i n e - 7 7 , and I o d i n e - 1 2 3 55 f o r m e t a b o l i c s t u d i e s o f t h e m y o c a r d i u m , C o m p a r a t i v e k i n e t i c s t u d i e s i n m i c e i n d i c a t e d e x t r a c t i o n o f t h e . o m e g a - f a t t y a c i d s t o be m o r e e f f i c i e n t t h a n t h e a l p h a - h a l o f a t t y a c i d s . Of t h e o m e g a - h a l o f a t t y a c i d s , 1 7 - i o d o h e p t a d e c e n o i c a c i d s h o w e d t h e h i g h e s t u p t a k e , w h i c h was c o m p a r a b l e t o ^ C - p a l m i t i c a c i d . The b e h a v i o r r o f a l p h a - h a l o f a t t y a c i d s was e x p l a i n e d by s t e a r i c h i n d r a n c e a n d / o r i n d u c t i v e e f f e c t s t h a t i n f l u e n c e d e s t e r i f i c a t i o n w i t h Coenzyme A and c a r n i t i n e a n d t h u s a f f e c t e d p a s s a g e t h r o u g h t h e mi t o - . c h o n d r i a l membrane ( M a c h u l l a e t a l . , 1 9 7 8 ) . T h i s was r e f l e c t e d i n t h e b l o o d a c t i v i t y . One m i n u t e a f t e r i n j e c t i o n o f a l p h a - b r o m o s t e a r i c a n d a l p h a - i o d o s t e a r i c a c i d s , 43% and 57% o f t h e t o t a l b l o o d a c t i v i t y was a s f r e e h a l i d e r e s p e c t i v e l y . I n c o n t r a s t , b y 1 m i n u t e p o s t - i n j e c t i o n o f t h e o m e g a - f a t t y a c i d , 100% o f t h e t o t a l b l o o d a c t i v i t y was f r e e h a l i d e ( M a c h u l l a e t a l . , 1 9 7 8 ) . Numerous i n v i t r o a n d i n v i v o s t u d i e s h a v e b e e n d o n e w i t h t h e 123 1 6 - I - h e x a d e c e n o i c a c i d . One d i s a d v a n t a g e i n u s i n g t e r m i n a l l y r a d i o i o d i n a t e d f a t t y a c i d a n a l o g s i s t h a t t h e m e t a b o l i s m i s e x t r e m e l y r a p i d , w i t h t h e r e s u l t o f I o d i d e - 1 2 3 b e i n g r e l e a s e d t o t h e b l o o d . T h i s i o d i d e i n c r e a s e s t h e b l o o d c o n c e n t r a t i o n a n d t h e r e f o r e d e c r e a s e s t h e t a r g e t / n o n - t a r g e t r a t i o f o r m y o c a r d i a l i m a g i n g . S t r u c t u r a l m o d i f i c a t i o n s o f f a t t y a c i d m o l e c u l e s may p r o v i d e an a n s w e r t o t h i s p r o b l e m . The m o d i f i c a t i o n m u s t be s u c h t h a t t h e m y o c a r d i a l e x t r a c t i o n o f t h e f a t t y a c i d w o u l d n o t be a f f e c t e d w h i l e t h e m e t a b o l i s m w i l l be d e c r e a s e d s o t h a t r a d i o a c t i v i t y r e m a i n s i n t h e h e a r t . The r a t e o f m e t a b o l i s m o f f a t t y a c i d s c o u l d be a f f e c t e d by : 1) s y n t h e s i s 56 o f b r a n c h c h a i n f a t t y a c i d s w h i c h r e s i s t b e t a - o x i d a t i o n 2) a t t a c h m e n t o f r a d i o i o d i n e t o an o m e g a - p h e n y l s u b s t i t u t e d f a t t y a c i d ( T h r a l l e t a l . , 1 9 7 8 ; Poe e t a l . , 1 9 7 7 ) . S u b s t i t u t i o n o f a f l u o r i n e a t o m f o r a h y d r o g e n a t o m a l o n g t h e c a r b o n c h a i n may p e r m i t r e t e n t i o n o f t h e b i o l o g i c a l b e h a v i o r a n d y e t d e t a i n m e t a b o l i s m o n c e i n s i d e t h e m y o c a r d i a l c e l l ( P o e e t a l . , 1 9 7 7 ) . The e f f e c t o f c h a i n l e n g t h on m y o c a r d i a l e x t r a c t i o n was d e m o n s t r a t e d u s i n g E r u c i c a c i d , an u n s a t u r a t e d 2 2 - c a r b o n f a t t y a c i d ( C h r i s t o p h e r s o n a n d B r e m e r , 1 9 7 2 ) . E r u r i c a c i d c o n c e n t r a t e d w i t h i n t h e m y o c a r d i u m b u t was m e t a b o l i z e d v e r y s l o w l y . B i l h e i m e r e t a l . ( 1 9 7 8 ) showed t h a t t h e r e i s i n c r e a s e d f a t t y a c i d a c c u m u l a t i o n a r o u n d t h e b o r d e r s o f a c u t e m y o c a r d i a l i n f a r c t s as e a r l y a s 6 h o u r s p o s t - o c c l u s i o n . By u s i n g a n o n m e t a b o l i z a b l e f a t t y - a c i d , t h e e f f e c t o f p h a r m a c o l o g i c i n t e r v e n t i o n on t h e e x t e n t o f r e c o v e r y o f m y o c a r d i a l c e l l s i n t h e a r e a s a r o u n d t h e i n f a r c t c o u l d be i n v e s t i g a t e d . I t a p p e a r s t h a t l a b e l e d f a t t y a c i d s c o u l d p r o v i d e d e t a i l e d i n f o r m a t i o n r e g a r d i n g t h e h e a r t s h o r t l y a f t e r m y o c a r d i a l o c c l u s i o n . S t r u c t u r a l m o d i f i c a t i o n s s h o u l d be i n v e s t i g a t e d i n an e f f o r t t o o b t a i n f a t t y a c i d s w h i c h w i l l p r o v i d e o p t i m a l b i o l o g i c a l b e h a v i o r f o r m y o c a r d i a l s c a n s . 56a EXPERIMENTAL METHODS AND MATERIALS 57 1 . A p p a r a t u s a ) R e f l u x A s s e m b l y A s t a n d a r d r e f l u x a s s e m b l y was u s e d w i t h a 25 ml r o u n d - b o t t o m f l a s k ( A c e G l a s s I n c o r p o r a t e d 1 4 / 2 0 , 110mm) a n d a 11cm, v e r t i c a l c o n d e n s e r . ( A c e G l a s s I n c o r p o r a t e d ) . A c o n s t a n t w a t e r and h e a t s u p p l y w e r e m a i n t a i n e d t h r o u g h o u t t h e r e f l u x i n g p e r i o d . b) A u t o m a t e d Gamma C o u n t e r - 1 1 8 5 The a u t o m a t e d gamma c o u n t e r was m a n u f a c t u r e d by N u c l e a r -C h i c a g o C o r p o r a t i o n (Des P l a i n e s , 1 1 1 . L o t 0 2 6 A ) a n d was a ' w e l l ' t y p e c o u n t e r w i t h a 3 i n c h s o d i u m i o d i d e ( T l a c t i v a t e d ) c r y s t a l . R a d i o a c t i v e s a m p l e s w e r e p l a c e d i n c o u n t i n g t u b e s ( 1 5 . 6 x 125 m m . , Amersham S e a r l e #00328) a n d c o u n t e d i n 4 p i d e t e c t i o n g e o m e t r y . C a l i b r a t i o n o f t h e Gamma C o u n t e r The gamma c o u n t e r was c a l i b r a t e d u s i n g a C s - 1 3 7 s o u r c e . ( A m e r s h a m - S e a r l e : .1 y C i + 1 0 % , M o d e l 1 8 4 6 4 2 ) U s i n g t h e p h o t o p e a k o f 6 6 2 K e V , t h e f i n e and t h e h i g h v o l t a g e s w e r e m a n i p u l a t e d u n t i l t h e p h o t o p e a k f e l l i n t h e 6 6 2 n d d i v i s i o n . T h e n , w i t h t h e a t t e n u a t o r s e t a t 8 , t h e h i g h v o l t a g e a t 8 0 0 , t h e f i n e v o l t a g e a t 1 0 , t h e s c a l e r e p r e s e n t e d l - 1 0 0 0 K e V . A S o d i u m I o d i d e - 1 3 1 s p e c t r u m was p l o t t e d t o e n s u r e t h a t t h e p h o t o p e a k was i n t h e 3 6 4 t h d i v i s i o n . F o r I o d i d e - 1 3 1 , t h e b a s e was s e t a t 3 0 0 , t h e w i n d o w a t 1 2 0 , a n d c o u n t e d on w i d e d i f f e r e n t i a l . Once c a l i b r a t e d , t h e gamma c o u n t e r was s t a b l e a n d s e l d o m d r i f t e d , a l t h o u g h r e c a l i b r a t i o n s w e r e done e v e r y 2 m o n t h s . 58 c ) T u b o r #8725 ( N u c l e a r - C h i c a g o ) The T u b o r was u s e d f o r t h e w h o l e - b o d y e x c r e t i o n s t u d i e s . The m a c h i n e c o n t a i n e d t w o - 3 i n c h N a l c r y s t a l s a n d was a l s o c a l i b r a t e d u s i n g a C s - 1 3 7 s o u r c e . A f t e r a d j u s t m e n t o f t h e h i g h a n d f i n e v o l t a g e s , t h e C s - 1 3 7 p e a k was i n c h a n n e l 6 6 2 . T h i s was a c h i e v e d w i t h t h e c o a r s e h i g h v o l t a g e a t 1 0 0 0 , t h e f i n e h i g h v o l t a g e a t 4 1 , a n d t h e a t t e n u a t o r a t 4 . An I o d i d e - 1 3 1 s o u r c e was u s e d t o e n s u r e t h a t t h e p h o t o p e a k was i n c h a n n e l 3 6 4 , w h i c h r e p r e s e n t e d 3 6 4 K e V . G e o m e t r y S t u d y o f t h e T u b o r The g e o m e t r i c a l d i f f e r e n c e s o f s h e l f l e v e l s a n d s p a c i a l p o s i t i o n i n g ( h o r i z o n t a l ' A ' o r v e r t i c a l ' B ' ) w e r e i n v e s t i g a t e d t o o b s e r v e a n y c h a n g e s i n c o u n t s p e r m i n u t e . A 7-ml v a c u t a i n e r ( B e c k t o n - D i c k i n s o n L t d . ) f i l l e d w i t h 60 u C i o f N a I - 1 3 1 w i t h w a t e r was u s e d t o s i m u l a t e t h e b o d y o f a m o u s e . C o u n t s w e r e r e c o r d e d f o r v a r i o u s s h e l f l e v e l s a s w e l l as f o r e a c h a x i a l d i r e c t i o n . C o n c e n t r i c c i r c l e s m a r k e d on t h e s h e l f e n s u r e d t h a t t h e v a c u t a i n e r was i n e x a c t l y t h e same p o s i t i o n f o r e a c h s h e l f l e v e l a n d a x i a l d i r e c t i o n . d) U n i - m e l t C a p i l l a r y M e l t i n g P o i n t A p p a r a t u s S a m p l e s w e r e p l a c e d i n c l o s e d - e n d m e l t i n g p o i n t c a p i l l a r y t u b e s • ( F i s h e r - S c i e n t i f i c Company) a n d s e t i n t h e a p p a r a t u s . The h e a t was r e g u l a t e d s o t h a t t h e t e m p e r a t u r e i n c r e a s e was s u c h as t o a l l o w v i s u a l i n s p e c t i o n o f t h e m e l t i n g p o i n t . e ) C h r o m a t o g r a p h y T a n k The c h r o m a t o g r a p h y t a n k was a s t a n d a r d g l a s s t a n k w i t h 59 d i m e n s i o n s o f 22 x 21 x 6 cm. f ) Gamma C a m e r a The gamma c a m e r a u s e d f o r t h e m y o c a r d i a l s c a n s was made by S e a r l e I n s t r u m e n t L t d . a n d was o f t h e LFOV t y p e . ( L a r g e F i e l d o f View)_ A h i g h e n e r g y c o l l i m a t o r was u s e d f o r t h e I o d i d e - 1 3 1 a n d t h e r a d i o i o d i n a t e d f a t t y a c i d s c a n s w h i l e a l o w - e n e r g y a l l p u r p o s e c o l l i m a t o r was u s e d f o r t h e T h a l l i u m - 2 0 1 s c a n . 2) C h e m i c a l s and R e a g e n t s a) F a t t y A c i d s ( i ) L a u r i e A c i d - E a s t m a n Kodak, L o t 9 3 3 , C P . g r a d e ( i i ) C a p r i c A c i d - E a s t m a n K o d a k , L o t 3 1 , T e c h n i c a l g r a d e ( i i i ) 2 - B r o m o t e t r a d e c a n o i c A c i d - F l u k a C h e m i s c h e , B 8 5 3 8 2 2 A G - P u r u m ( i v ) 9 - c i s T e t r a d e c e n o i c A c i d - S i g m a C o . , S t . L o u i s , M i s s o u r i , (99% p u r e ) ( v ) 1 0 - B r o m o c a p r i c A c i d - S a p o n L a b o r a t o r i e s , B l o o m b u r y , N . J . ( 9 5 - 9 9 % p u r e ) ( v i ) 1 2 - B r o m o l a u r i c A c i d - S a p o n L a b o r a t o r i e s , B l o o m b u r y , N . J . ( 9 5 - 9 9 % p u r e ) b) S o l v e n t s ( i ) A c e t o n e N . F . ( i i ) E t h e r S o l v e n t U . S . P . ( i i i ) H e x a n e - a n a l y t i c a l g r a d e - M a i 1 i n c k r o d t , L o t ASN ( i v ) A c e t i c A c i d - m a d e f r o m G l a c i a l a c e t i c a c i d , r e a g e n t ACS 60 B a k e r a n d A d a m s o n , A l l i e d C h e m i c a l s , C a n a d a ( v ) A l c o h o l 9 5 % - c o m m e r i c a l g r a d e ( v i ) B e n z e n e - r e a g e n t g r a d e ( v i i ) P e t r o l e u m E t h e r - 3 0 / 6 0 ( v i i i ) C y c l o h e x a n e - p r a c t i c a l g r a d e ( i x ) NaOH-l N C e r t i f i e d F i s h e r S c i e n t i f i c C o . , L o t 770410 ( 1 . 0 0 1 0 - ' . ' 9 9 9 5 N) ( x ) P r o p y l e n e G l y c o l - U . S . P . , B . D . H . L o t 3 5 0 5 6 c ) 1-131 ( N a l ) N a I - 1 3 1 was s u p p l i e d b y A t o m i c E n e r g y o f C a n a d a L t d . , C o m m e r c i a l P r o d u c t s , O t t a w a . I t s r a d i o c h e m i c a l p u r i t y was s t a t e d t o be n o t l e s s t h a n 9 5 % . The I o d i d e - 1 3 1 was c a r r i e r f r e e a n d no r e d u c i n g a g e n t s w e r e a d d e d . N a l was p r o v i d e d i n Na2S0^ l i q u i d . d) Normal S e r u m A l b u m i n (human) (HSA) HSA was s u p p l i e d by C o n n a u g h t L a b . L t d . , W i l l o w d a l e , O n t a r i o , a n d was p r o d u c e d b y c o l d e t h a n o l p l a s m a f r a c t i o n a t i o n . I t c o n t a i n e d 25gm o f n o r m a l human s e r u m a l b u m i n p e r 100 ml o f d i l u e n t . The d i l u e n t c o n t a i n e d . 0 2 M Na A c e t y l t r y p t o p h a n a t e a n d . 0 2 M Na c a p r y l a t e . e ) G e l man I T L C - S G S h e e t s G e l m a n I T L C - S G s h e e t s w e r e s u p p l i e d by t h e Gelman I n s t r u m e n t C o m p a n y - 5 x 2 0 c m . . , Ann A r b o r , M i c h i g a n , L o t 2 0 2 3 8 . f ) G e l m a n I T L C - S A F S h e e t s The p o l y s i l i c i c a c i d g e l i m p r e g n a t e d w i t h g l a s s f i b r e s h e e t s w i t h f l u o r e s c e n t i n d i c a t o r w e r e s u p p l i e d f r o m t h e Gelman I n s t r u m e n t .61 C o m p a n y , 5 x 2 0 c m , Ann A r b o r , M i c h i g a n , L o t 5 1 4 3 6 . g) B i o g e l P - 1 0 B i o g e l P - 1 0 was s u p p l i e d by t h e B i o r a d L a b o r a t o r i e s , R i c h m o n d , C a l i f o r n i a . ( E x c l u s i o n l i m i t , 2 0 , 0 0 0 d a l t o n s , 1 0 0 - 2 0 0 mesh) L o t 1 6 8 7 0 2 . h) B i o r a d AG T - X 8 The a n i o n e x c h a n g e r e s i n was s u p p l i e d by t h e B i o r a d L a b o r a t o r i e s , R i c h m o n d , C a l i f o r n i a . ( 1 0 0 - 2 0 0 m e s h - - C h l o r i d e f o r m ) i ) N o r m a l S a l i n e S o d i u m C h l o r i d e I n j e c t i o n , U . S . P . , A b b o t t , L o t 1 5 8 3 , p H - 5 . 7 . j ) B a c t e r i o s t a t i c H2O f o r I n j e c t i o n W a t e r f o r i n j e c t i o n was s u p p l i e d by A b b o t t L a b o r a t o r i e s L t d . , M o n t r e a l , C a n a d a . L o t 3 9 7 7 . k) P h e n o t h a l e i n - B . P . , U . S . P . f r o m BDH ( C a n a d a L t d , L o t 547321 ) P h e n o t h a l e i n T . S . - P r e p a r e d a c c o r d i n g t o U . S . P . XVII 1) Bromo C r e s o l G r e e n - 3 ' , 3 ' 5 , 5 ' . - T e t r a b r o m o - m - c r e s o l s u l f o n p h t h a l e i n B r o m o c r e s o l g r e e n was s u p p l i e d by P h a r m a c e u t i c L a b o r a t o r i e s , A l l i e d C h e m i c a l a n d Dye C o r p . N . Y . L o t 1 5 6 6 1 . m) R h o d a m i n e B R h o d a m i n e B was o b t a i n e d f r o m BDH C h e m i c a l s L t d . , P o o l e , E n g l a n d , L o t 1 1 0 7 3 2 0 . n ) N e m b u t a l 60mg/ml ( f o r V e t e r n a r y Use O n l y ) N e m b u t a l i n j e c t i o n was s u p p l i e d by A b b o t t L a b . L t d . ( C h e m i c a l a n d A g r i c u l t u r e P r o d u c t s d i v i s i o n ) L o t 8 7 7 6 0 NA. 62 3 . F a t t y A c i d A n a l y s i s a ) P u r i t y o f t h e B r o m i n a t e d F a t t y - A c i d A n a l o g s The f a t t y a c i d a n a l o g s w e r e s t a t e d t o be 9 5 - 9 9 % p u r e by GC a n a l y s i s . H o w e v e r , r o u t i n e t e s t s w e r e p e r f o r m e d t o c h e c k f o r d e g r a d a t i o n a n d e n s u r e c h e m i c a l p u r i t y . ( i ) M e l t i n g P o i n t s F i v e m e l t i n g p o i n t d e t e r m i n a t i o n s w e r e done f o r e a c h f a t t y a c i d a n a l o g a n d t h e r e s u l t s a v e r a g e d a n d c o m p a r e d t o t h o s e r e p o r t e d i n t h e 1 i t e r a t u r e . ( i i ) T h i n L a y e r C h r o m a t o g r a p h y ( T L C ) TLC was p e r f o r m e d f o r e a c h b r o m i n a t e d f a t t y a c i d a n a l o g a n d i t s c o r r e s p o n d i n g p h y s i o l o g i c f a t t y a c i d . The s o l u t i o n s c o n t a i n e d lOmg/ml f a t t y a c i d i n a c e t o n e . T w e n t y m i c r o l i t r e s o f e a c h s o l u t i o n was c h r o m a t o g r a p h e d on ! I T L C - S A , a n d I T L C - S A F s t r i p s . The c h r o m a t o g r a m s w e r e a i r d r i e d a n d d e v e l o p e d t o a h e i g h t o f 1 0 - 1 2 cm i n f o u r d i f f e r e n t d e v e l o p i n g s o l v e n t s y s t e m s . ( 1 ) H e x a n e : d i e t h y l e t h e r r a c e t i c a c i d ( 8 0 : 2 0 : 1 ) ( 2 ) P e t r o l e u m e t h e r : d i e t h y l e t h e r : a c e t i c a c i d ( 7 0 : 3 0 : 1 ) ( 3 ) B e n z e n e : d i e t h y l e t h e r : a c e t i c a c i d ( 7 5 : 2 5 : 1 ) ( 4 ) C y c l o h e x a n e Once d e v e l o p e d , t h e s o l v e n t f r o n t s w e r e m a r k e d a n d t h e s t r i p s a l l o w e d t o a i r d r y . S e v e r a l d e t e c t i n g r e a g e n t s w e r e u s e d t o i n d i c a t e t h e m i g r a t i o n o f t h e f a t t y a c i d a s w e l l as t h e f a t t y a c i d a n a l o g s . R f v a l u e s w e r e c a l c u l a t e d f o r e a c h s p o t . 6 3 The d e t e c t i n g r e a g e n t s u s e d i n c l u d e d i o d i n e v a p o r , b r o m o c r e s o l g r e e n . 5 % , a n d r h o d a m i n e - B . I o d i n e v a p o r was u s e d a s a g e n e r a l r e a g e n t t o v i s u a l i z e o r g a n i c c o m p o u n d s . B r o m o c r e s o l g r e e n was p r e p a r e d i n an e t h a n o l i c s o l u t i o n a n d a d j u s t e d t o pH 6 . F a t t y a c i d s a p p e a r e d . a s y e l l o w s p o t s a g a i n s t a b a c k g r o u n d o f g r e e n - b l u e . W i t h c h r o m a t o g r a m s s p r a y e d w i t h r h o d a m i n e - B a n d s u b j e c t e d t o e i t h e r l o n g o r s h o r t u l t r a v i o l e t r a y s , f a t t y a c i d s a p p e a r e d a s f l u o r e s c e n t o r a n g e s p o t s a g a i n s t a b a c k g r o u n d o f b r o w n i s h - o r a n g e . b) P r e p a r a t i o n o f R a d i o i o d i n a t e d F a t t y A c i d s ( i ) 9 - I o d o t e t r a d e c a n o i c A c i d 9-?.cis f ' e t r a d e c e n o i c a c i d was r a d i o i o d i n a t e d u s i n g t h e i o d i n e m o n o c h l o r i d e m i c r o s c a l e m e t h o d d e v e l o p e d by R o b i n s o n a n d L e e ( 1 9 7 5 ) . In t h i s r e a c t i o n , t h e i o d i n e a d d s a c r o s s t h e d o u b l e b o n d on t h e n i n t h c a r b o n , w h i l e t h e c h l o r i d e a d d s on t o t h e t e n t h c a r b o n ; t h u s y i e l d i n g a s a t u r a t e d r a d i o i o d i n a t e d f a t t y a c f d t ( i i ) 2 - I o d o t e t r a d e c a n o i c A c i d , 1 0 - I o d o c a p r i c A c i d , a n d 1 2 - I o d o l a u r i c  A c i d T h e s e r a d i o i o d i n a t e d f a t t y a c i d s w e r e p r e p a r e d by r e f l u x i n g N a I - 1 3 1 w i t h t h e b r o m o c a r b o x y l i c a c i d s i n o r d e r f o r t h e i n t e r - h a l o g e n a t i o n r e p l a c e m e n t t o o c c u r . T h i s m e t h o d was a l s o d e v e l o p e d by R o b i n s o n and L e e ( 1 9 7 5 ) . The p r o c e d u r e i n c l u d e d d i s s o l v i n g l O m g , o f t h e b r o m o c a r b o x y l i c a c i d i n 10 m l , , o f a c e t o n e i n t h e r e f l u x a p p a r a t u s . B o i l i n g c h i p s a n d a c a l c u l a t e d amount o f N a I - 1 3 1 was a d d e d a n d t h e m i x t u r e r e f l u x e d . I n 64 o r d e r t o d e t e r m i n e a m i n i m a l r e f l u x i n g t i m e c o u p l e d w i t h a h i g h r a d i o -c h e m i c a l y i e l d , d i f f e r e n t r e f l u x i n g t i m e p e r i o d s w e r e c o n s i d e r e d . I n a d d i t i o n , t h e q u a n t i t y o f t h e • b r o m o c a r b o x y l i c a c i d as w e l l a s t h e v o l u m e o f N a I - 1 3 1 was v a r i e d . c ) A n a l y s i s o f R a d i o c h e m i c a l Y i e l d R a d i o c h e m i c a l y i e l d was d e t e r m i n e d by c h r o m a t o g r a p h y on Gelman I T L C - S G s t r i p s . A p p r o x i m a t e l y 20 u l , o f t h e s o l u t i o n was s p o t t e d , a i r d r i e d , a n d d e v e l o p e d i n a s o l v e n t s y s t e m o f h e x a n e : d i e t h y l e t h e r ; a c e t i c a c i d ( 8 0 : 2 0 : 1 ) . A f t e r 10 m i n u t e s , t h e c h r o m a t o g r a m s w e r e r e m o v e d , t h e s o l v e n t f r o n t s m a r k e d , a n d a l l o w e d t o a i r d r y . U s i n g t h i s d e v e l o p i n g s y s t e m , f r e e i o d i d e was s e p a r a t e d d i s t i n c t l y f r o m t h e r a d i o i o d i n a t e d f a t t y a c i d s . The l o c a t i o n o f t h e f r e e i o d i d e - 1 3 1 was c o n f i r m e d by u s i n g a s o l u t i o n o f N a I - 1 3 1 i n a c e t o n e a n d t h e same c h r o m a t o g r a p h y s y s t e m . The l o c a t i o n s ; o f t h e r a d i o i o d i n a t e d f a t t y a c i d s w e r e a s c e r t a i n e d by i o d i n e v a p o r . The c h r o m a t o g r a m was t h e n c u t i n t o 1cm.: s e g m e n t s f r o m t h e o r i g i n t o l c m . ; p a s t t h e s o l v e n t f r o n t . The sum o f a l l t h e c o u n t s a f t e r b a c k g r o u n d c o r r e c t i o n r e p r e s e n t e d 100% a c t i v i t y . The f r e e i o d i d e - 1 3 1 was r e t a i n e d a t . t h e o r i g i n w h i l e t h e r a d i o i o d i n a t e d f a t t y a c i d s t r a v e l l e d w i t h t h e s o l v e n t f r o n t . d) P r e p a r a t i o n o f t h e R a d i o i o d i n a t e d F a t t y A c i d - A l b u m i n S o l u t i o n A f t e r d e t e r m i n a t i o n o f t h e r a d i o c h e m i c a l y i e l d , t h e r a d i o i o d i n a t e d f a t t y a c i d a c e t o n e s o l u t i o n was e v a p o r a t e d t o d r y n e s s u n d e r a s t r e a m o f d r y N i t r o g e n g a s . T h r e e m l . , o f 25% Human S e r u m A l b u m i n was a d d e d a n d t h e 65 r e s u l t a n t m i x t u r e was s t i r r e d w i t h a m a g n e t i c s t i r r e r u n t i l c o m p l e t e d i s s o l u t i o n . e ) Removal o f F r e e I o d i d e - 1 3 1 The r a d i o i o d i n a t e d f a t t y a c i d a l b u m i n m i x t u r e was l a y e r e d on an a n i o n e x c h a n g e c o l u m n w h i c h c o n s i s t e d o f a 3ml , s y r i n g e f i l l e d w i t h B i o r a d A - X 8 . T h i s c o l u m n h a d b e e n p r e - s a t u r a t e d w i t h a 6% s o l u t i o n o f HSA. As t h e m i x t u r e f l o w e d t h r o u g h t h e c o l u m n , f r e e i o d i d e a n d b r o m i d e w e r e r e t a i n e d . The c o l u m n was t h e n e l u t e d w i t h 3 m l . o f n o r m a l s a l i n e a n d t h e e f f l u e n t a d j u s t e d t o a 6% HSA s o l u t i o n by a d d i t i o n o f n o r m a l s a l i n e . S t e r i l i t y was o b t a i n e d by p a s s i n g t h e f i n a l p r e p a r a t i o n t h r o u g h a . 2 2 m i c r o n m i l l i p o r e f i l t e r . V e r i f i c a t i o n o f t h e a b s e n c e o f f r e e i o d i d e - 1 3 1 was d o n e by g e l p e r m e a t i o n c h r o m a t o g r a p h y u s i n g a 10 cm _x 1 c m , c o l u m n o f B i o - g e l P - 1 0 . The c o l u m n was a l s o e l u t e d w i t h p h y s i o l o g i c s a l i n e . f ) A n a l y s i s o f t h e S t a b i l i t y o f t h e R a d i o i o d i n a t e d F a t t y A c i d i n 6%  Human S e r u m A l b u m i n The s t a b i l i t y o f t h e r a d i o i o d i n a t e d f a t t y a c i d s i n 6% HSA was d e t e r m i n e d f o r 7 d a y s . The p r e p a r a t i o n was k e p t r e f r i g e r a t e d f o r t h e t i m e p e r i o d . To c h e c k f o r h y d r o l y s i s o f i o d i d e - 1 3 1 , a l i q u o t s o f t h e p r e p a r a t i o n w e r e a n a l y z e d i n an a n i o n - e x c h a n g e c o l u m n a n d by a g e l p e r m e a t i o n c o l u m n d a i l y . 4 . A n i m a l s a ) M i c e M a l e CD 1 S w i s s m i c e w e i g h i n g 1 8 - 3 0 gm a n d b e i n g 4 - 6 w e e k s 66 o l d w e r e u s e d t h r o u g h o u t t h e d i s t r i b u t i o n , e x c r e t i o n , a n d t o x i c i t y s t u d i e s . On a r r i v a l f r o m t h e UBC a n i m a l u n i t , 25 a n i m a l s w e r e a c c l i m a t i z e d f o r 24 h o u r s i n m e t a l c a g e s w i t h d i m e n s i o n s o f 30 x 50 cm_. L o b o u n d b e d d i n g ( P a x t o n P r o c e s s i n g L t d . , P a x t o n , 1 1 1 . ) was u s e d , ;and P u r i n a Mouse Chow a n d t a p w a t e r w e r e s u p p l i e d a d In" b i t u r n . P r i o r t o i n j e c t i o n , 5 - 6 m i c e w e r e r a n d o m l y s e l e c t e d f o r e a c h e x p e r i m e n t a l g r o u p a n d p l a c e d i n p l a s t i c c a g e s w i t h t h e same p r o v i s i o n s a s m e n t i o n e d a b o v e . b) R a b b i t s F o r t h e m y o c a r d i a l s c a n s , New Z e a l a n d m a l e w h i t e r a b b i t s w e i g h i n g 2 - 2 . 5 Kg: , w e r e u s e d . The r a b b i t s w e r e f e d P u r i n a R a b b i t Chow a n d g i v e n t a p w a t e r ad l i b i t u m . They w e r e h o u s e d i n m e t a l c a g e s . 5 . T i s s u e D i s t r i b u t i o n S t u d i e s I n o r d e r t o e v a l u a t e t h e l o c a l i z a t i o n o f t h e r a d i o i o d i n a t e d f a t t y a c i d s , .1 ml o f e a c h p r e p a r a t i o n was i n j e c t e d by t a i l v e i n i n t o g r o u p s o f m i c e . . A t t h e t i m e o f t h e i n j e c t i o n s , t h r e e .1 ml s t a n d a r d s o f e a c h r a d i o i o d i n a t e d f a t t y a c i d w e r e p r e p a r e d . The mean o f t h e c o u n t s o b t a i n e d f r o m t h e s t a n d a r d s a p p r o x i m a t e d t h e amount o f r a d i o a c t i v i t y i n j e c t e d . By c o u n t i n g t h e s e s t a n d a r d s s i m u l t a n e o u s l y w i t h t h e mouse s a m p l e s , i t was u n n e c e s s a r y t o a c c o u n t f o r d e c a y . F i v e m i c e w e r e u s e d t o s t u d y d i s t r i b u t i o n a t e a c h t i m e p e r i o d a n d t h e mean a s w e l l as t h e s t a n d a r d e r r o r was c a l c u l a t e d f o r e a c h g r o u p o f m i c e f o r e a c h o r g a n . The t i m e p e r i o d s c o n s i d e r e d i n c l u d e d : 67 1 , 2 , 3 , 4 , 5 , 6 , 8 , . 1 0 , 1 5 , 2 0 , 2 5 , 3 0 , 4 0 , 5 0 , 60 m i n u t e s , a n d 1 , 2 , 3 , 4 , 6 , 1 2 , a n d 24 h o u r s . F o l l o w i n g a p r e - d e t e r m i n e d t i m e p e r i o d p o s t - i n j e c t i o n , t h e m i c e w e r e a n e s t h e t i z e d w i t h e t h e r , w e i g h e d , a n d b e h e a d e d . The b l o o d was c o l l e c t e d , t h e v o l u m e m e a s u r e d , a f t e r w h i c h i t was p l a c e d i n a c o u n t i n g t u b e . The t a i l s w e r e r e m o v e d and p l a c e d i n c o u n t i n g t u b e s a s w e l l . The t a i l c o u n t s w e r e s u b t r a c t e d f r o m t h e s t a n d a r d s i n o r d e r t o d e d u c e t h e t r u e a m o u n t o f a c t i v i t y w h i c h e n t e r e d t h e b o d y o f t h e m o u s e . The p e r c e n t i n j e c t e d d o s e r e m a i n i n g i n t h e t a i l was u s u a l l y l e s s t h a n 2%. I f t h e c o u n t s f r o m t h e t a i l w e r e g r e a t e r t h a n 2 % , t h e r e s u l t s f r o m t h a t p a r t i c u l a r mouse was r e j e c t e d a n d a n a d d i t i o n a l mouse u s e d . The m i c e w e r e d i s s e c t e d u s i n g m i d s t e r n a l a n d a b d o m i n a l i n c i s i o n s . The o r g a n s e x c i s e d i n c l u d e d t h e h e a r t , l u n g , l i v e r , k i d n e y s , s p l e e n , a d r e n a l s , g a l l b l a d d e r , s t o m a c h , l a r g e a n d s m a l l i n t e s t i n e s , b o n e , a n d m u s c l e . The c o n t e n t s o f t h e s t o m a c h a n d i n t e s t i n e s w e r e e m p t i e d a n d t h e o r g a n s r i n s e d s e v e r a l t i m e s w i t h n o r m a l s a l i n e a n d b l o t t e d d r y . The b o n e s a m p l e c o n s i s t e d o f t h e f e m u r , s c r a p e d c l e a n o f m u s c l e a n d f a t w h i l e t h e m u s c l e s a m p l e was a p o r t i o n o f t h e q u a d r i c e p s e x t e n s o r . A l l t h e t i s s u e s a m p l e s w e r e b l o t t e d f r e e o f b l o o d a n d k e p t m o i s t u n t i l t h e y w e r e w e i g h e d . The e n t i r e s u r g i c a l p r o c e d u r e a s w e l l a s t h e w e i g h i n g r e q u i r e d l e s s t h a n 15 m i n u t e s , a f t e r w h i c h t h e s a m p l e s w e r e c o u n t e d i n t h e gamma c o u n t e r . The a c t i v i t y l o c a l i z e d i n e a c h o r g a n was e x p r e s s e d i n 3 w a y s : (1) P e r c e n t D o s e / O r g a n ( 2 ) P e r c e n t Dose/Gm O r g a n 6 8 ( 3 ) P e r c e n t Dose/Gm O r g a n P e r c e n t D o s e / m l B l o o d 6 . T o x i c i t y S t u d i e s The t o x i c i t y s t u d i e s w e r e done w i t h t h e b r o m o - f a t t y a c i d s s i n c e a n y t o x i c e f f e c t s w o u l d p r o b a b l y n o t be a t t r i b u t e d by t h e s m a l l number o f r a d i o i o d i n a t e d f a t t y a c i d m o l e c u l e s . The LD^g ( l e t h a l d o s e - 5 0 ) . w a s c a l c u l a t e d by t h e m e t h o d o f L i t c h f i e l d a n d W i l c o x i n ( 1 9 4 9 ) a f t e r a s i n g l e i n t r a v e n o u s i n j e c t i o n . The l o w s o l u b i l i t y o f t h e b r o m i n a t e d f a t t y a c i d s i n 6% HSA was a l i m i t i n g f a c t o r i n t h a t t h e h i g h e s t c o n c e n t r a t i o n o b t a i n e d was 2 m g / m l . A t t h i s d o s e , i n j e c t i o n s by t a i l v e i n o f up t o 1 ml d i d n o t e l i c i t a n y t o x i c symptoms o r d e a t h s . T h e r e f o r e d i f f e r e n t m e t h o d s w e r e e m p l o y e d t o a c h i e v e a h i g h e r c o n c e n t r a t i o n o f f a t t y a c i d . I t m u s t be k e p t i n m i n d , h o w e v e r , t h a t t h e s e v e h i c l e s w e r e n o t i d e n t i c a l t o t h e 6% HSA u s e d i n t h e d i s t r i b u t i o n a n d e x c r e t i o n s t u d i e s . a) P r e p a r a t i o n o f S o d i u m B r o m o l a u r a t e . The s o d i u m s a l t o f b r o m o l a u r i c a c i d was p r e p a r e d a c c o r d i n g t o t h e m e t h o d o f Van H a r k e n e t a l . ( 1 9 6 9 ) . A 20 m l , , c o l d s o l u t i o n o f 25% HSA, c o o l e d t o 5 ° C i n an i c e b a t h , was a d d e d t o a h o t s o l u t i o n o f b r o m o l a u r a t e i n 15 ml n o r m a l s a l i n e . The f i n a l c o n c e n -t r a t i o n o b t a i n e d was 1 0 m g , / m l b r o m o l a u r a t e i n 10% HSA. T h i s c o n c e n t r a t i o n was c h o s e n s o t h a t a t t h e l o w e r d o s e s , no p h a r m a c o l o g i c e f f e c t s w e r e e l i c i t e d , w h i l e a t h i g h d o s e s , t h e f i n a l t o x i c e f f e c t was d e a t h . A f t e r i n j e c t i o n , t h e a n i m a l s w e r e o b s e r v e d f o r 7 d a y s . 69 b) P r e p a r a t i o n o f B r o m o c a p r i c A c i d S o l u t i o n I t was n o t p o s s i b l e t o make s t a b l e c o m p l e x e s o f b r o m o c a p r i c a c i d i n a l b u m i n a t h i g h c o n c e n t r a t i o n s o f t h e b r o m o c a p r i c s a l t . The b r o m o c a p r a t e p r e c i p i t a t e d o u t o f s o l u t i o n . T h e r e f o r e , an i n j e c t a b l e m i x t u r e b a s e d on t h e f o l l o w i n g f o r m u l a was u s e d : B r o m o c a p r i c M i x t u r e B r o m o c a p r i c A c i d 500 m g , E t h a n o l 95% 5 ml P r o p y l e n e G l y c o l 11 ml H2O f o r i n j e c t i o n q . s . 30 ml The f i n a l b r o m o c a p r i c a c i d c o n c e n t r a t i o n was 1 6 . 6 7 m g - : / m l . A g a i n , a s f o r t h e b r o m o l a u r a t e , i n c r e m e n t d o s e s w e r e i n j e c t e d t o g r o u p s o f s i x m i c e by t a i l v e i n a n d t h e a n i m a l s w e r e o b s e r v e d f o r 7 d a y s . 7 . W h o l e B o d y E x c r e t i o n W h o l e b o d y c o u n t i n g was p e r f o r m e d on m i c e i n j e c t e d b y t a i l v e i n t o d e t e r m i n e t h e d e c r e a s e i n t o t a l b o d y a c t i v i t y w i t h t i m e . The w h o l e b o d y e x c r e t i o n c u r v e p r o v i d e d an i n d i c a t i o n o f t h e e x c r e t i o n r a t e o f t h e r a d i o i o d i n a t e d f a t t y a c i d s b y t h e m i c e . The i n j e c t i o n v o l u m e s w e r e k e p t c o n s t a n t a t .1 m l . I m m e d i a t e l y a f t e r i n j e c t i o n , e a c h mouse was p l a c e d i n a p l a s t i c c o n t a i n e r w i t h d i m e n s i o n s o f 7 x 5 x 3 . 6 cm. w h i c h was t h e n p o s i t i o n e d i n a l a r g e r c o n t a i n e r l i n e d w i t h t r i p a d s . The s m a l l e r c o n t a i n e r was u s e d t o r e s t r i c t t h e movements o f t h e mouse w h i l e t h e l a r g e r c o n t a i n e r was u s e d t o p r e v e n t c o n t a m i n a t i o n o f t h e T u b o r . E a c h mouse was c o u n t e d i m m e d i a t e l y a f t e r i n j e c t i o n a n d a t t h e f o l l o w i n g t i m e i n t e r v a l s : 5 , 1 0 , 2 0 , 3 0 , 4 0 , 5 0 , 6 0 , 7 0 , 8 0 , 9 0 , 1 0 0 , 1 2 0 , 70 1 4 0 , 1 6 0 , 1 8 0 , 2 1 0 , 2 4 0 , 2 7 0 , 3 0 0 , 3 3 0 , 3 6 0 , 3 9 0 , 4 2 0 , 4 5 0 , 4 8 0 , 5 1 0 , 540 5 7 0 , 6 0 0 , 6 3 0 , 6 6 0 , 7 2 0 , 1 4 4 0 , 2 8 8 0 , 4 3 2 0 , 5 7 6 0 , a n d 8 6 4 0 m i n u t e s . E a c h mouse was c o u n t e d f o r 1 m i n u t e a n d c o r r e c t e d f o r b a c k g r o u n d . On r e m o v a l f r o m t h e c o u n t i n g c o n t a i n e r s , t h e m i c e w e r e p r o m p t e d t o u r i n a t e . They w e r e t h e n p l a c e d i n c a g e s w i t h m e t a l g r i d s a n d g i v e n f o o d a n d w a t e r a d l i b i t u m . The m e t a l g r i d s p r o v i d e d a p l a t f o r m w h i c h p r e v e n t e d t h e c o n t a m i n a t i o n o f t h e m i c e by e x c r e t a . 8 . C o m p a r t m e n t a l A n a l y s i s The c o r r e c t e d c o u n t s f r o m t h e w h o l e b o d y e x c r e t i o n s t u d y w e r e p l o t t e d on s e m i - l o g p a p e r v e r s u s t i m e . The a c t i v i t y was e x p r e s s e d a s a p e r c e n t a g e o f t h e t o t a l a c t i v i t y , o r t h e a c t i v i t y i n t h e mouse i m m e d i a t e l y a f t e r i n j e c t i o n . C o m p u t e r a n a l y s i s was done u s i n g t h e n o n - 1 i n p r o g r a m . W e i g h t i n g , a m e t h o d o f a d d e d e m p h a s i s t o c e r t a i n d a t a p o i n t s , was b a s e d on t h e number o f a n i m a l s f o r t h e t r i a l d i v i d e d by t h e s t a n d a r d d e v i a t i o n s q u a r e d . The c u r v e s w e r e f i t t e d u s i n g a o n e , t w o , t h r e e , a n d f o u r c o m p a r t m e n t m o d e l . The c u r v e o f b e s t f i t was a n a l y z e d by t h e c o m p u t e r , a g r a p h d r a w n , a n d t h e s l o p e s c a l c u l a t e d f o r e a c h c o m p a r t m e n t . 9 . E x c r e t i o n A n a l y s i s I n o r d e r t o a n a l y z e t h e u r i n a r y a n d f e c a l e x c r e t i o n o f t h e r a d i o i o d i n a t e d f a t t y a c i d s , m i c e w e r e i n j e c t e d w i t h .1 ml o f e a c h p r e p a r a t i o n . A f t e r i n j e c t i o n , t h e m i c e w e r e c o u n t e d i n t h e T u b o r . S u b s e q u e n t l y , e a c h mouse was p l a c e d i n a n i n d i v i d u a l 1000 ml b e a k e r w i t h a p l a t f o r m c o n s i s t i n g o f a w i r e g r i d ( 8 mm s q u a r e ) u n d e r w h i c h - t h e r e 71 was a f i n e w i r e m e s h . The p u r p o s e o f t h i s a s s e m b l y was t o e f f e c t i v e l y s e p a r a t e t h e f e c e s f r o m t h e u r i n e . The f e c e s w e r e r e t a i n e d by t h e mesh w h i l e t h e u r i n e f e l l t h r o u g h t h e mesh o n t o t h e b e a k e r . A t s e l e c t e d t i m e i n t e r v a l s o f 6 , 9 , a n d 12 h o u r s p o s t -i n j e c t i o n , w h o l e b o d y c o u n t i n g was r e p e a t e d . T h r e e m i c e w e r e u s e d f o r e a c h t i m e i n t e r v a l . To a c c o u n t f o r t h e t o t a l a c t i v i t y , t h e m o u s e , t h e u r i n e , a s w e l l a s t h e f e c e s w e r e c o u n t e d . A g a i n , s t a n d a r d s w e r e c o u n t e d s i m u l t a n e o u s l y w i t h t h e s a m p l e s s o t h a t d e c a y c o r r e c t i o n w o u l d n o t be n e c e s s a r y . Due t o t h e e x t r e m e l y c o n c e n t r a t e d u r i n e o f t h e m i c e , i t was n e c e s s a r y t o make a d i l u t i o n , m e a s u r e t h e t o t a l v o l u m e , a n d c o u n t an a l i q u o t . A p p r o x i m a t e l y 20 p 1 o f e a c h u r i n e s a m p l e was c h r o m a t o g r a p h e d on Gelman I T L C - S G i n a d e v e l o p i n g s o l v e n t o f h e x a n e : d i e t h y l e t h e r : a c e t i c a c i d ( 8 0 : 2 0 : 1 ) . The c h r o m a t o g r a p h y s t r i i p s w e r e d e v e l o p e d a n d t r e a t e d a s p r e v i o u s l y d e s c r i b e d . To a s c e r t a i n t h e f o r m i n w h i c h t h e r a d i o i o d i n a t e d f a t t y a c i d s w e r e e x c r e t e d , s t a n d a r d s w e r e made u s i n g m i c e u r i n e w h i c h w e r e s p i k e d w i t h I o d i d e - 1 3 1 i n 6% H S A , o r t h e r a d i o i o d i n a t e d f a t t y a c i d i n 6% HSA. I n a d d i t i o n , a g r o u p o f m i c e - w e r e - i n j e c t e d w i t h t h e I o d i d e - 1 3 1 i n 6% HSA s o l u t i o n , a n d t h e u r i n e a l s o c h r o m a t o g r a p h e d . A n a l y s i s o f t h e f e c e s w e r e n o t a t t e m p t e d a s i t was a p p a r e n t t h a t m o s t o f t h e r a d i o a c t i v i t y w a s . r e c o v e r e d i n t h e u r i n e . A n a l y s i s o f f e c e s w o u l d e n t a i l a v e r y l e n g t h y p r o c e d u r e o f h o m o g e n i z a t i o n a n d a s e r i e s o f e x t r a c t i o n s . Due t o t h e n a t u r e o f t h e weak i o d i d e - c a r b o n b o n d , t h e a n a l y t i c a l p r o c e d u r e i t s e l f c o u l d c o n c e i v a b l y s p l i t t h e i o d i d e - c a r b o n b o n d , i f i t was s t i l l i n t a c t i n t h e f e c e s . 72 1 0 . The R a d i o n u c l i d e S c a n The s c a n s w e r e done u s i n g a S e a r l e (LFOV) gamma c a m e r a made by t h e S e a r l e I n s t r u m e n t L t d . l o c a t e d i n t h e N u c l e a r M e d i c i n e D e p a r t m e n t o f V a n c o u v e r G e n e r a l H o s p i t a l . O u t p u t c o n s i s t e d o f c o n v e n t i o n a l X - r a y f i l m w h i c h a c c u m u l a t e d c o u n t s u n t i l a c e r t a i n p r e d e t e r m i n e d c o u n t was r e a c h e d . The r a b b i t s w e r e a n e s t h e t i z e d w i t h 25mg / k g o f N e m b u t a l i n j e c t i o n p r i o r t o s c a n n i n g . T h e y w e r e p l a c e d i n t h e p r o n e p o s i t i o n on t h e f a c e o f t h e gamma c a m e r a , s o t h a t t h e s c a n s o b t a i n e d w e r e a n t e r i o r v i e w s . Once p o s i t i o n e d o n t h e c a m e r a , t h e r a b b i t s w e r e i n j e c t e d w i t h t h e r a d i o l a b e l e d s o l u t i o n s by e a r v e i n . TABLE I R a d i o a c t i v i t y I n j e c t e d f o r M y o c a r d i a l S c a n s S c a n mCi i n j e c t e d 1-131 (HSA) 1 . 7 0 1-131 l a u r i c a c i d 1 . 9 7 1-131 c a p r i c a c i d 1 . 7 5 T l - 2 0 1 1 . 0 0 72a IV RESULTS AND DISCUSSIONS 7 3 .1. A n a l y s i s o f t h e B r o m i n a t e d F a t t y A c i d A n a l o g s a) M e l t i n g P o i n t s o f t h e B r o m i n a t e d F a t t y A c i d A n a l o g s A s e r i e s o f m e l t i n g p o i n t s w e r e d e t e r m i n e d f o r e a c h b r o m o -c a r b o x y l i c a c i d . M e l t i n g p o i n t s w e r e n o t t a k e n f o r t h e 9 r e i s -t e t r a d e c e n o i c a c i d . TABLE I I M e l t i n g P o i n t s o f t h e B r o m i n a t e d F a t t y A c i d A n a l o g s A c i d R e p o r t e d M e l t i n g A c t u a l l y M e l t i n g P o i n t (8 C) P o i n t ( ° C) 2 - B r o m o t e t r a d e c a n o i c 4 1 . 5 4 4 ( s h a r p ) 1 0 - B r o m o c a p r i c 4 2 . 0 3 9 - 4 0 . 5 1 2 - B r o m o l a u r i c 5 3 . 0 5 1 . 5 ( s h a r p ) A l t h o u g h t h e m e l t i n g p o i n t s o b s e r v e d v a r i e d f r o m t h e r e p o r t e d l i t e r a t u r e v a l u e s , t h e s e r e s u l t s c o u l d be i n f l u e n c e d by t h e m e l t i n g p o i n t a p p a r a t u s u s e d . More i n d i c a t i v e o f p u r i t y o f t h e compounds i s how s h a r p t h e m e l t i n g p o i n t s a r e . From t h i s d a t a , i t a p p e a r e d t h a t t h e 2 - b r o m o t e t r a d e c a n o i c a c i d and t h e 1 2 - b r o m o l a u r i c a c i d w e r e v e r y p u r e due t h e i r v e r y s h a r p m e l t i n g p o i n t s . The I Q - b r o m o c a p r i c a c i d , h o w e v e r , h a d a s m a l l r a n g e i n t h e m e l t i n g p o i n t s , t h u s i n d i c a t i n g t h e p r e s e n c e o f some i m p u r i t y . T h i s i m p u r i t y was n o t q u a n t i t a t e d . 74 b) C h r o m a t o g r a p h y o f t h e B r o m i n a t e d F a t t y A c i d A n a l o g s a n d t h e P h y s i o l o g i c F a t t y A c i d s TABLE I I I R e v a l u e s o f F a t t y A c i d s a n d T h e i r A n a l o g s U s i n g V a r i o u s D e t e c t i n g R e a g e n t s 3 F a t t y A c i d s R f V a l u e s I o d i n e R h o d a m i n e B r o m o c r e s o l V a p o r B G r e e n 1 2 - B r o m o l a u r i c A c i d . 9 6 . 9 5 . 9 6 L a u r i e A c i d . 9 7 . 9 6 . 9 6 1 0 - B r o m o c a p r i c A c i d . 9 7 . 9 3 . 9 5 C a p r i c A c i d . 9 8 . 9 5 . 9 6 ' H e x a n e : d i e t h y l e t h e r : a c e t i c . a c i d . ( 8 0 : 2 0 : 1 ) U s i n g t h i s d e v e l o p i n g s y s t e m o f h e x a n e : d i e t h y l e t h e r : a c e t i c a c i d , t h e f a t t y a c i d s t r a v e l l e d w i t h t h e s o l v e n t f r o n t s , w h e r e a s t h e f r e e i o d i d e r e m a i n e d a t t h e o r i g i n . W i t h a l l t h r e e d e t e c t i n g r e a g e n t s u s e d , t h e r e was o n l y o n e d i s t i n c t s p o t a t t h e s o l v e n t f r o n t i n d i c a t i v e o f t h e f a t t y a c i d w i t h no e v i d e n c e o f t a i l i n g . T h e R f v a l u e s f o r t h e b r o m i n a t e d f a t t y a c i d s w e r e s i m i l a r t o t h e p h y s i o l o g i c f a t t y a c i d s . S i n c e a l l t h r e e d e t e c t i n g r e a g e n t s p r o v i d e d c o n s i s t e n t v i s u a l i d e n t i f i c a t i o n o f t h e f a t t y a c i d s a n d t h e i r a n a l o g s , w i t h f a i r l y c o n s i s t e n t Rf v a l u e s , i t was d e c i d e d t o u s e o n l y one d e t e c t i n g r e a g e n t f o r t h e o t h e r d e v e l o p i n g s o l v e n t s . B r o m o c r e s o l G r e e n was c h o s e n . I o d i n e v a p o r was somewhat l i m i t e d i n t h a t t h e c o l o r f a d e d v e r y q u i c k l y on e x p o s u r e t o a i r w h i l e w i t h R h o d a m i n e B , i t was n e c e s s a r y t o u s e a UV s o u r c e . 75 TABLE IV Rf1,. V a l u e s o f F a t t y A c i d s a n d T h e i r A n a l o g s U s i n g V a r i o u s D e v e l o p i n g S o l v e n t s 1 F a t t y A c i d s R f V a l u e s U s i n g B r o m o c r e s o l G r e e n D e v e l o p i n g S y s t e m s ( 1 ) ( 2 ) (1L 1 2 - B r o m o l a u r i c A c i d . 9 7 . 9 3 . 2 0 L a u r i e A c i d . 9 7 . 9 5 . 3 5 1 0 - B r o m o c a p r i c A c i d . 9 6 . 9 3 . 1 6 C a p r i c A c i d 1 . 9 6 . 9 4 . 3 4 ^ P e t r o l e u m e t h e r : d i e t h y l e t h e r : a c e t i c a c i d ( 7 0 : 3 0 : 1 ) ( 2 ) v 1 B e n z e n e : d i e t h y l e t h e r : a c e t i c a c i d ( 7 5 : 2 5 : 1 ) ( 3 ) C y c l o h e x a n e W i t h s y s t e m ( 3 ) , c y c l o h e x a n e , t h e r e was s e v e r e t a i l i n g o f a l l t h e s a m p l e s . The p h y s i o l o g i c f a t t y a c i d s m i g r a t e d a p p r o x i m a t e l y d o u b l e t h e d i s t a n c e o f t h e b r o m i n a t e d f a t t y a c i d a n a l o g s . T h i s was n o t a g o o d d e v e l o p i n g s y s t e m f o r f a t t y a c i d s . I t a p p e a r e d t h a t t h e a d d i t i o n o f s m a l l a m o u n t s o f a c e t i c a c i d p r e v e n t e d t h e t a i l i n g o f t h e f a t t y a c i d s . The o t h e r t h r e e d e v e l o p i n g s y s t e m s s h o w e d s i m i l a r R f v a l u e s f o r t h e f a t t y a c i d s when d e t e c t e d by b r o m o c r e s o l g r e e n . The f a t t y a c i d s as w e l l as t h e i r a n a l o g s a p p e a r e d t o be r e l a t i v e l y p u r e a s o n l y one d i s t i n c t s p o t c o u l d be d e t e c t e d f o r e a c h f a t t y a c i d i n t h e d i f f e r e n t d e v e l o p i n g s o l v e n t s y s t e m s . 76 2 . The R a d i o i o d i n a t i o n P r o c e d u r e s a ) 9 - I o d o t e t r a d e c a n o i c A c i d The i o d i n e m o n o c h l o r i d e m i c r o s c a l e m e t h o d o f R o b i n s o n a n d Lee ( 1 9 7 5 ) p r o v i d e d v e r y p o o r r e s u l t s . A l t h o u g h t h i s m e t h o d was a t t e m p t e d i n e x c e s s o f 100 t r i a l s , r e s u l t s w e r e i n c o n s i s t e n t w i t h v e r y l o w r a d i o -c h e m i c a l y i e l d s . The a m o u n t s o f t h e i n d i v i d u a l r e a g e n t s w e r e v a r i e d i n an e f f o r t t o i n c r e a s e t h e f i n a l y i e l d . H o w e v e r , t h e p r o b l e m c o u l d n o t be s o l v e d a n d t h e r e a c t i o n was s t i l l u n p r e d i c t a b l e . S i n c e t h e i o d i n e monochl o r i de a d d i t i o n r e a c t i o n b e g i n s w i t h an u n s a t u r a t e d f a t t y a c i d a n d r e s u l t s i n a s a t u r a t e d f a t t y a c i d , i t was d e c i d e d t o s e a r c h f o r a 1 4 - c a r b o n u n s a t u r a t e d f a t t y a c i d w h i c h a l r e a d y h a d a b r o m i n e s u b s t i t u t e d f o r a h y d r o g e n a t o m a l o n g t h e h y d r o c a r b o n c h a i n . In t h i s m a n n e r , r a d i o i o d i n a t i o n c a n be a c h i e v e d by an i n t e r h a l o g e n r e p l a c e m e n t . T h i s f a t t y a c i d a n a l o g was f o u n d i n 2 - b r o m o t e t r a d e c a n o i c a c i d , w h i c h was a v a i l a b l e c o m m e r c i a l l y . b) 2 - I o d o t e t r a d e c a n o i c A c i d , 1 0 - I o d o c a p r i c A c i d , a n d 1 2 - I o d o - L a u r i c A c i d The r a d i o i o d i n a t i o n o f t h e b r o m i n a t e d f a t t y a c i d a n a l o g s w a s . e a s i l y a c h i e v e d by r e f l u x i n g w i t h a r a d i o a c t i v e i o d i n e s o u r c e . R a d i o i o d i n a t i o n was f a i r l y r a p i d , w h i l e t h e r e s u l t s w e r e much h i g h e r a n d t h e r e a c t i o n much more c o n s i s t e n t t h a n t h e a t t e m p t s w i t h t h e i o d i n e m o n o c h l o r i d e m i c r o s c a l e m e t h o d . 77 c ) O p t i m i z a t i o n o f t h e R a d i o i o d i n a t i o n P r o c e d u r e ( i ) R a d i o c h e m i c a l y i e l d s o f R a d i o i o d i n a t e d F a t t y A c i d s i n t h e  A b s e n c e o f H e a t I t was o f i n t e r e s t t o d e t e r m i n e t h e r a d i o c h e m i c a l y i e l d o f r a d i o i o d i n a t e d f a t t y a c i d s i n t h e a b s e n c e o f h e a t . T h i s was d o n e by e x p e r i m e n t s c a r r i e d o u t u n d e r t h e i d e n t i c a l c o n d i t i o n s w i t h t h e e x c e p t i o n o f r e f l u x i n g . TABLE V The E f f e c t o f Time On t h e R a d i o c h e m i c a l Y i e l d s o f  R a d i o i o d i n a t e d F a t t y A c i d s (No R e f l u x i n g ) R a d i o c h e m i c a l Y i e l d s (%) A c i d 1 h o u r 2 h o u r s 3 h o u r s 4 h o u r s I o d o l a u r i c A c i d 1 . 1 0 1 . 6 8 2 . 7 4 6 . 2 1 I o d o c a p r i c A c i d 0 . 8 7 2 . 1 4 3 . 2 1 5 . 0 7 I t was a p p a r e n t t h a t h e a t was m a n d a t o r y f o r t h e i n t e r h a l o g e n e x c h a n g e . The r a d i o c h e m i c a l y i e l d s o b t a i n e d w i t h o u t r e f l u x i n g w e r e e x c e p t i o n a l l y l o w , w i t h a maximum o f a p p r o x i m a t e l y 6% i n 4 h o u r s by TLC a n a l y s i s . ( i i ) R a d i o c h e m i c a l Y i e l d s o f R a d i o i o d i n a t e d F a t t y A c i d s i n t h e  P r e s e n c e o f H e a t In t h e e x p e r i m e n t s w h e r e h e a t was s u p p l i e d by r e f l u x i n g , t h e f o l l o w i n g r e a c t i o n o c c u r r e d : B r ( C H 2 ) n C 0 0 H + 1 3 1 I " / 1 3 1 1 ( C H ^ C O O H + B r " I n a n a l y s i s , t h e r a d i o c h e m i c a l y i e l d a p p e a r e d t o i n c r e a s e w i t h t h e 78 F i g u r e 2 R a d i o c h e m i c a l Y i e l d s o f R a d i o i o d i n a t e d F a t t y A c i d s by B r o m i n e R e p l a c e m e n t 79 r e f l u x i n g t i m e u n t i l a b o u t f o u r h o u r s , a t w h i c h t i m e t h e c u r v e p l a t e a u e d . ( F i g u r e 2) M a x i m a l r a d i o c h e m i c a l y i e l d s w e r e 93% a n d 97% f o r 1 2 - i o d o l a u r i c a n d 1 0 - i o d o c a p r i c a c i d s r e s p e c t i v e l y w i t h 4 h o u r s o f r e f l u x i n g . R a d i o -c h e m i c a l y i e l d s a t r e f l u x i n g t i m e s o f up t o 12 h o u r s w e r e e s s e n t i a l l y t h e same a s t h o s e o b s e r v e d a f t e r 4 h o u r s o f r e f l u x i n g . The r a d i o c h e m i c a l y i e l d s v a r i e d m a r g i n a l l y f o r t h e two r a d i o i o d i n a t e d f a t t y a c i d s . The r a d i o c h e m i c a l y i e l d o f 1 0 - i o d o c a p r i c a c i d a p p e a r e d s l i g h t l y g r e a t e r t h a n t h a t o f t h e 1 2 - i o d o l a u r i c a c i d , t h u s b e i n g i n a g r e e m e n t w i t h t h e o b s e r v a t i o n o f R o b i n s o n a n d L e e ( 1 9 7 5 ) t h a t t h e r e was a d e c r e a s e o f l a b e l i n g r a t e s a n d r a d i o c h e m i c a l y i e l d w i t h i n c r e a s i n g m o l e c u l a r w e i g h t . The o b s e r v e d d i f f e r e n c e may be s m a l l a s t h e two f a t t y a c i d s u n d e r c o n s i d e r a t i o n o n l y v a r i e d by two c a r b o n u n i t s . ( i i i ) R a d i o c h e m i c a l Y i e l d s o f t h e R a d i o i o d i n a t e d F a t t y A c i d s  U s i n g V a r i a b l e Q u a n t i t i e s o f t h e B r o m i n a t e d F a t t y A c i d s  a n d N a I - 1 3 1 . The l a b e l i n g r e a c t i o n s u t i l i z e d lOmg o f t h e b r o m i n a t e d f a t t y a c i d s i n i t i a l l y a n d , a s a r e s u l t , a c o n s i d e r a b l e amount o f u n l a b e l e d f a t t y a c i d w o u l d a l s o be a d m i n i s t e r e d i n t r a v e n o u s l y t o t h e e x p e r i m e n t a l a n i m a l s . I n o r d e r t o r e d u c e t h e amount o f u n l a b e l e d f a t t y a c i d a d m i n i s t e r e d , i t was d e c i d e d t o d e c r e a s e t h e i n i t i a l a m o u n t o f b r o m i n a t e d f a t t y a c i d u s e d f o r t h e r e f l u x i n g . H o w e v e r , i n e x p e r i m e n t s when 5 m g , o f t h e b r o m i n a t e d f a t t y a c i d s w e r e u s e d , t h e r a d i o c h e m i c a l y i e l d s w e r e c o n s i d e r a b l y l o w e r w i t h 4 h o u r s o f r e f l u x i n g . The maximum r a d i o c h e m i c a l y i e l d s w e r e o n l y a b o u t 55% f o r b o t h r a d i o i o d i n a t e d f a t t y a c i d s . C o n s e q u e n t l y , i t was d e c i d e d t o p r o c e e d w i t h lOrng, o f t h e 8 0 b r o m i n a t e d f a t t y a c i d s i n i t i a l l y f o r t h e r e f l u x i n g . The u s e o f d i f f e r e n t v o l u m e s o f N a I - 1 3 1 d i d n o t a p p e a r t o a f f e c t t h e r a d i o c h e m i c a l y i e l d s i g n i f i c a n t l y a s l o n g as t h e v o l u m e u s e d was l e s s t h a n .1 m l . ( T a b l e 6 ) TABLE VI The E f f e c t o f V a r i a b l e V o l u m e s o f N a I - 1 3 1 on t h e  R a d i o c h e m i c a l Y i e l d s o f R a d i o i o d i n a t e d F a t t y A c i d s A c i d R a d i o c h e m i c a l y i e l d (%) w i t h 4 h o u r s r e f l u x i n g . 0 5 ml , .10ml.? . 2 0 m U . 5 0 m l . 1 ml I o d o l a u r i c A c i d 90 90 72 61 50 I o d o c a p r i c A c i d 92 91 76 70 65 From T a b l e 6 , i t a p p e a r e d t h a t i n v o l u m e s o f g r e a t e r t h a n .1 ml o f N a I - 1 3 1 , t h e r e may be some h y d r o l y s i s o f t h e h a l o g e n f r o m t h e f a t t y a c i d , t h u s l e a d i n g t o a l o w e r e d r a d i o c h e m i c a l y i e l d . d ) A n a l y s i s o f t h e S t a b i l i t y o f t h e R a d i o i o d i n a t e d F a t t y A c i d s  i n 6% Human S e r u m A l b u m i n The s t a b i l i t y o f t h e t e r m i n a l r a d i o i o d i n a t e d f a t t y a c i d s w i t h r e s p e c t t o h y d r o l y s i s i n 6% HSA u n d e r c o n d i t i o n s o f r e f r i g e r a t i o n was d e t e r m i n e d . L i b e r a t i o n o f f r e e I o d i d e - 1 3 1 was a n a l y z e d by b o t h a n i o n e x c h a n g e a n d g e l p e r m e a t i o n c h r o m a t o g r a p h y a n d t h e r e s u l t s a r e p r e s e n t e d i n F i g u r e 3 . The r e l a t i v e s t a b i l i t y o f t h e r a d i o i o d i n a t e d f a t t y a c i d s was s t u d i e d f o r 7 d a y s . B o t h r a d i o i o d i n a t e d f a t t y a c i d s a p p e a r e d t o be F i g u r e 3 S t a b i l i t y o f R a d i o i o d i n a t e d F a t t y A c i d s i n 67o Human S e r u m A l b u m i n 82 s t a b . l e f t f o r t h e f i r s t 2 d a y s , a f t e r w h i c h t h e p e r c e n t a g e o f r a d i o i o d i n a t e d f a t t y a c i d d r o p p e d b e l o w 9 0 % . The 1 0 - i o d o c a p r i c a c i d seemed more s u s c e p t i b l e t o h y d r o l y s i s as t h e i n t a c t r a d i o i o d i n a t e d a c i d d e c r e a s e d a t a f a s t e r r a t e , a s n o t e d by t h e s t e e p e r s l o p e . ( F i g u r e 3) T h i s may be a r e f l e c t i o n o f t h e s t r e n g t h o f t h e c a r b o n - i o d i d e b o n d . A l t h o u g h r a d i o -i o d i n a t i o n a p p e a r e d m a r g i n a l l y h i g h e r f o r t h e 1 0 - i o d o c a p r i c a c i d , p e r h a p s t h e b o n d f o r m e d was n o t as s t r o n g a s t h e c a r b o n - i o d i d e b o n d o f 1 2 - n ' : o d o l a u r i c a c i d . U s i n g b o t h t h e a n i o n e x c h a n g e c o l u m n a n d t h e g e l p e r m e a t i o n c o l u m n , t h e r e s u l t s w e r e s i m i l a r f o r e a c h r a d i o i o d i n a t e d f a t t y a c i d The d a y o f r e f l u x i n g was n o t e d a s d a y 0 , i n w h i c h t h e r a d i o a c t i v i t y p r e s e n t was t a k e n t o be 100%. The p r e p a r a t i o n s w e r e u s e d f o r t h e f o l l o w i n g one o r two d a y s t o e n s u r e t h e a b s e n c e o f f r e e i o d i d e - 1 3 1 , w h i c h c o u l d a l t e r t h e b i o l o g i c a l d i s t r i b u t i o n s t u d i e s a s w e l l a s t h e s c a n . 3 . P r e l i m i n a r y D i s t r i b u t i o n S t u d i e s o f 1 0 - I o d o c a p r i c , 1 2 n I o d o - L a u r i c , a n d 2 - I o d o t e t r a d e c a n o i c A c i d s ' P r e l i m i n a r y d i s t r i b u t i o n s t u d i e s w e r e p e r f o r m e d u s i n g t h e a b o v e m e n t i o n e d r a d i o i o d i n a t e d f a t t y a c i d s i n m i c e . From F i g u r e 4 , w h i c h d e p i c t e d t h e r a d i o p h a r m a c e u t i c a l c o n c e n t r a t i o n w i t h i n t h e h e a r t , i t was a p p a r e n t t h a t 1 2 - i o d o l a u r i c a c i d was c o n c e n t r a t e d t o t h e g r e a t e s t e x t e n t . T h i s was f o l l o w e d b y 1 0 - i o d o c a p r i c a c i d a n d t h e n by 2 - i o d o t e t r a d e c a n o i c a c i d . The m y o c a r d i a l c o n c e n t r a t i o n o f 2 - i o d o t e t r a d e c a n o i c a c i d was a b o u t h a l f o f t h a t o f t h e o t h e r two r a d i o i o d i n a t e d f a t t y a c i d s . T h i s a p p a r e n t l a c k o f u p t a k e o f • 7 l o d o t * t r o d « c o A o t c O 10 l o d o d * c o n o i c * 12 l o d o l o u r i c T i m * ( h o u r t ) Figure 4 Total Myocardial Uptake of 2-Iodotetradecanoic Acid, 10-Iododecanoic Acid, and 12-Iodolauric Acid in Mice CO CO Radioactivity levels have been determined even after metabolism of the fatty acid. 84 2 - i o d o t e t r a d e c a n o i c , a c i d c a n be a t t r i b u t e d t o s t e a r i c h i n d r a n c e , a s n o t e d by R o b i n s o n a n d Lee ( 1 9 7 5 ) . The l a r g e b u l k y i o d i n e m o l e c u l e h a s t h e r a d i u s o f a m e t h y l g r o u p a n d p r o j e c t s o u t o f t h e p l a n e o f t h e f a t t y a c i d m o l e c u l e , t h u s d e c r e a s i n g t h e m y o c a r d i a l u p t a k e . ( R o b i n s o n a n d L e e , 1 9 7 5 ) . The m y o c a r d i a l c o n c e n t r a t i o n o f a l l t h r e e r a d i o i o d i n a t e d f a t t y a c i d a n a l o g s d e c r e a s e d r a p i d l y w i t h t i m e . By 30 m i n u t e s p o s t - i n j e c t i o n , t h e p e r c e n t i n j e c t e d d o s e r e m a i n i n g i n t h e m y o c a r d i u m was l e s s t h a n . 5 % . The same t r e n d was o b s e r v e d i n t h e % d o s e / g m o r g a n ( F i g u r e 5) a n d t h e % d o s e / g m o r g a n / % d o s e / m l b l o o d . ( F i g u r e 6 ) A l t h o u g h t h e h i g h e s t t o t a l m y o c a r d i a l u p t a k e was by 1 2 - i o d o l a u r i c a c i d , when c a l c u l a t e d on t h e % d o s e / g m . b a s i s , 1 0 - i o d o c a p r i c a c i d was c o n c e n -t r a t e d t o a g r e a t e r e x t e n t . 2 - i o d o t e t r a d e c a n o i c a c i d was c l e a r l y i n f e r i o r t o t h e o t h e r two i o d i n a t e d f a t t y a c i d s i n a l l a s p e c t s i n v e s t i -g a t e d a n d t h u s was e x c l u d e d f r o m f u r t h e r s t u d i e s . a ) P r e l i m i n a r y R a d i o n u c l i d e S c a n S c a n s w e r e a t t e m p t e d u s i n g t h e P i c k e r N u c l e a r D y n a c a m e r a t o a s s e s s t h e p o t e n t i a l u s e f u l n e s s o f t h e two t e r m i n a l r a d i o i o d i n a t e d f a t t y a c i d s a s m y o c a r d i a l s c a n n i n g a g e n t s . S c a n s w e r e t a k e n i m m e d i a t e l y a f t e r an i n t r a v e n o u s i n j e c t i o n o f 1 2 - i o d o l a u r i c a c i d a n d a c c u m u l a t e d t o 1 0 0 0 c o u n t s . The s c a n s s h o w e d some b a c k g r o u n d a c t i v i t y . The l i v e r a n d h e a r t w e r e o u t l i n e d a l t h o u g h t h e y w e r e i n d i s t i n g u i s h a b l e f r o m one a n o t h e r . I n a d d i t i o n , t h e r e was p r o b a b l y some c o n t r i b u t i n g a c t i v i t y f r o m t h e l u n g s . The g a s t r o i n t e s t i n a l t r a c t was f a i n t l y v i s u a l i z e d a t t h e b e g i n n i n g o f s c a n n i n g , b u t became more e v i d e n t a s t h e s c a n p r o g r e s s e d . • 2 lodot - t t rotUtonoic o 10 Io4od«conoit * 13 lotfolewric F i g u r e 5 R e l a t i v e M y o c a r d i a l U p t a k e o f 2 - I o d o t e t r a d e c a n o i c A c i d , 1 0 - I o d o d e c a n o i c A c i d , a n d 1 2 - I o d o l a u r i c A c i d i n M i c e a a R a d i o a c t i v i t y l e v e l s h a v e b e e n d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . F i g u r e 6 M y o c a r d i a l / B l o o d D i s t r i b u t i o n o f 2 - I o d o t e t r a d e c a n o i c A c i d , 1 0 - I o d o d e c a n o i c A c i d , a n d 1 2 - I o d o l a u r i c A c i d i n M i c e a R a d i o a c t i v i t y l e v e l s h a v e been d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . 87 From t h e i n i t i a l s c a n s , t h e r e a p p e a r e d t o be e v i d e n c e o f m y o c a r d i a l u p t a k e , a l t h o u g h t h e u p t a k e was n o t d e f i n i t i v e . I t was d e c i d e d t h a t a gamma c a m e r a w i t h a h i g h e n e r g y c o l l i m a t o r w o u l d p r o v i d e b e t t e r r e s o l u t i o n a n d more d e f i n i t i v e s c a n s . 4 . T i s s u e D i s t r i b u t i o n 131 131 The t i s s u e d i s t r i b u t i o n o f I - c a p r . i c a c i d , I - l a u r i c a c i d , as w e l l as N a I - 1 3 1 i n 6% Human S e r u m A l b u m i n was s t u d i e d as a f u n c t i o n o f t i m e i n g r o u p s o f m i c e . A p p r o x i m a t e l y . 5 u C i o f r a d i o -a c t i v i t y was a d m i n i s t e r e d by t a i l v e i n t o e a c h mouse a n d t h e t i s s u e d i s t r i b u t i o n was done u s i n g t h e p r o c e d u r e p r e v i o u s l y d e s c r i b e d . I n t h e d i s t r i b u t i o n s t u d i e s , t h e p r i m a r y o r g a n o f i n t e r e s t was t h e h e a r t . H o w e v e r , due t o t h e a n a t o m i c a l l o c a t i o n o f t h e h e a r t , i t was i m p e r a t i v e t o c o n s i d e r o t h e r o r g a n s w h i c h w e r e i n t h e i m m e d i a t e v i c i n i t y as w e l l . T h e s e o r g a n s i n c l u d e d t h e l i v e r , t h e l u n g s , a n d t h e s t o m a c h . S i n c e t h e s e o r g a n s a r e h i g h l y v a s c u l a r and a r e c o m p a r a t i v e l y l a r g e i n s i z e , t h e r a d i o p h a r m a c e u t i c a l c o u l d l o c a l i z e t o a c o n s i d e r a b l e e x t e n t , t h u s i n t e r f e r i n g w i t h t h e i m a g i n g o f t h e m y o c a r d i u m . F o r t a b u l a t i o n s o f t h e r a d i o a c t i v i t y d i s t r i b u t e d t h r o u g h o u t t h e e n t i r e mouse b o d y , a s s u m p t i o n s w e r e made t h a t 45% o f t h e body w e i g h t r e p r e s e n t e d m u s c l e , 6% c o r r e s p o n d e d t o b o n e , a n d 7 7 . 8 m l . p e r Kg r e p r e s e n t e d t h e t o t a l b l o o d v o l u m e ( W i s h e t a l . , 1 9 5 0 ; S t a n d e t a l . , 1 9 6 2 ) . O t h e r o r g a n s c o n s i d e r e d i n c l u d e d t h e k i d n e y s , t h e s p l e e n , t h e s t o m a c h , t h e l a r g e a n d s m a l l i n t e s t i n e s , t h e g a l l b l a d d e r , as w e l l as t h e a d r e n a l s . The maximum c o n c e n t r a t i o n o f r a d i o p h a r m a c e u t i c a l by 88 t h e g a l l b l a d d e r a n d t h e a d r e n a l s was l e s s t h a n .1% o f t h e i n j e c t e d d o s e , t h u s t h e r e s u l t s w e r e e x c l u d e d . a ) 1 3 1 I - C a p r i c A c i d 1 31 The r e s u l t s o f t h e o r g a n d i s t r i b u t i o n s t u d i e s f o r I - c a p n c a c i d , e x p r e s s e d as " p e r c e n t i n j e c t e d d o s e p e r t o t a l o r g a n " o f t h e s p l e e n , s t o m a c h , i n t e s t i n e s , m u s c l e , a n d bone a r e l i s t e d i n T a b l e 7 , w h i l e t h e g r a p h i c a l p r e s e n t a t i o n o f t h e " p e r c e n t i n j e c t e d d o s e p e r t o t a l o r g a n " o f t h e b l o o d , h e a r t , l u n g s , l i v e r a n d k i d n e y s a r e shown i n F i g u r e 7 . From t h e s e r e s u l t s , i t a p p e a r e d t h a t t h e c o n c e n t r a t i o n o f t h e r a d i o p h a r m a -c e u t i c a l i n t h e o r g a n s e x a m i n e d w e r e t h e h i g h e s t i m m e d i a t e l y f o l l o w i n g i n j e c t i o n , a f t e r w h i c h t h e r e was a s t e a d y d e c l i n e w i t h t i m e . 1 31 The h i g h e s t m y o c a r d i a l u p t a k e o f I - c a p r i c a c i d o c c u r r e d w i t h i n t h e f i r s t f e w m i n u t e s a f t e r i n j e c t i o n . The d i s a p p e a r a n c e o f r a d i o a c t i v i t y f r o m t h e h e a r t o c c u r r e d i n an e x p o n e n t i a l m a n n e r . T h e r e a p p e a r e d t o be t h r e e c o m p o n e n t s . The f i r s t c o m p o n e n t a p p e a r e d e x t r e m e l y r a p i d , w i t h i n t h e f i r s t f e w m i n u t e s f o l l o w i n g i n j e c t i o n , a f t e r w h i c h t h e r e was a somewhat s l o w e r s e c o n d c o m p o n e n t , f o l l o w e d by w h a t a p p e a r e d t o be a s t e a d y - s t a t e j w h e r e t h e c o n c e n t r a t i o n i n t h e m y o c a r d i u m r e m a i n e d a l m o s t c o n s t a n t . The f i r s t as w e l l a s t h e s e c o n d c o m p o n e n t may be i n d i c a t i v e o f m y o c a r d i a l o x i d a t i o n o f t h e f a t t y a c i d . I t i s known t h a t o n c e t h e . f a t t y a c i d s a r e w i t h i n t h e m y o c a r d i a l c a l l s , t h e y a r e d e g r a d e d by B e t a o x i d a t i o n t o p r o v i d e e n e r g y ( O l i v e r , 1 9 7 6 ; R o b i n s o n a n d L e e , 1 9 7 5 ; S p i l t e r a n d S p i t z e r , 1 9 7 1 ) . The d e g r a d a t i o n T A B L E V I I T o t a l U p t a k e o f 1 3 1 I - C a p r i c A c i d b y t h e S p l e e n , S t o m a c h L a r g e a n d S m a l l I n t e s t i n e s , M u s c l e , a n d B o n e o f M i c e a , b T i m e ( h o u r s ) S p l e e n S t o m a c h I n t e s t i n e s M u s c l e 0 B o n e d . 0 1 7 • 2 4 ± . 0 2 . 7 6 ± . l l 2 . 9 5 + . 0 9 1 6 . 2 6 ± 1 . 8 3 . 0 2 + . . 3 2 . 0 3 3 . 3 0 ± . 0 3 . 9 3 ± . 1 5 2 . 9 9 ± . 1 0 1 6 . 8 2 ± . 9 2 3 . 2 3 ± . 1 3 . 0 5 0 . 3 2 ± . 0 2 1 . 2 1 ± . l l 2 . 7 0 ± . 1 6 1 6 . 1 2 ± . 5 8 3 . 5 5 ± . 1 2 . 0 6 7 . 3 5 ± . 0 1 1 . 3 4 ± . 2 0 2 . 8 6 ± . 1 0 1 7 . 8 7 ± . 9 3 3 . 4 9 ± . 1 2 . 0 8 3 . 3 7 + . 0 4 1 . 4 4 ± . 2 0 2 . 7 2 ± . 1 8 1 9 . 0 2 ± . 6 2 3 . 9 0 ± . 1 6 . 1 0 0 . 2 8 + . 0 2 1 . 6 2 ± . 1 7 2 . 8 9 ± . l l 1 6 . 6 8 ± . 8 2 3 . 7 4 ± . 2 0 . 1 3 3 . 3 8 + . . 0 1 2 . 7 3 ± . 3 8 2 . 8 7 ± . U 1 4 . 5 5 ± . 8 5 3 . 4 6 ± . 1 2 . 1 6 7 . 2 9 ± . 0 2 2 . 3 4 ± . 4 7 2 . 5 5 ± . 1 7 1 2 . 0 U . 4 2 3 . 1 0 + . . 2 3 . 2 5 0 . 2 9 ± . 0 2 2 . 6 3 ± . 3 2 2 . 6 2 + . 2 9 1 2 . 4 4 ± . 5 6 2 . 7 4 ± . 1 3 . 3 3 3 . 2 7 ± . 0 2 2 . 2 1 ± . 4 8 2 . 4 2 ± . 1 7 1 1 . 8 9 ± . 7 2 2 . 6 9 ± . 0 9 . 4 1 7 . 2 9 + . 0 4 3 . 1 6 ± . 3 4 2 . 1 U . 0 7 1 2 . 0 4 ± . 6 2 2 . 5 5 ± . 2 0 . 5 0 0 . 1 8 ± . 0 1 3 . 4 6 ± . 2 2 1 . 9 7 ± . 0 8 1 0 . 8 3 ± . 7 8 2 . 1 8 + . . 1 3 . 6 6 7 . 1 9 ± . 0 2 2 . 8 6 ± . 4 0 1 . 8 6 ± . 2 2 9 . 7 3 + . 7 5 2 . 3 9 ± . 1 7 . 8 3 3 . 1 6 ± . 0 2 2 . 9 5 ± . 2 9 1 . 6 9 ± . 1 7 7 . 6 5 ± . 7 1 1 . 8 1 ± . 1 4 1 . 0 0 0 . 1 8 ± . 0 6 3 . 0 2 ± . 9 1 1 . 5 0 ± . 1 9 7 . 6 0 ± . 9 3 1 . 6 8 ± . 2 6 2 . 0 0 0 . 1 0 ± . 0 1 2 . 0 U . 2 8 . 9 7 ± . 1 3 6 . 8 9 ± . 4 1 1 . 2 8 ± . 1 0 4 . 0 0 0 . 0 5 + . 0 0 4 1 . 0 6 + . 2 7 . 5 5 ± . 0 5 2 . 8 8 ± . 4 1 . 6 U . 0 7 6 . 0 0 0 . 0 6 ± . 0 1 1 . 2 6 ± . 3 0 . 7 4 ± . 1 3 3 . 2 0 ± . 4 1 . 6 9 ± . 1 3 1 2 . 0 0 0 . 0 0 6 + . 0 0 1 . 0 6 ± . 0 2 . 0 6 ± . 0 1 1 . 3 5 ± . 1 3 . 1 2 ± . 0 1 2 4 . 0 0 0 . 0 0 5 ± . 0 0 1 . 0 4 + . 0 1 . 0 6 ± . 0 1 1 . 4 8 ± . 1 0 . 1 0 ± . 0 1 CO a E x p r e s s e d a s p e r c e n t i n j e c t e d ^ I - c a p r i c a c i d p e r t o t a l o r g a n k M e a n v a l u e s f r o m f i v e m i c e ± s t a n d a r d e r r o r o f t h e m e a n c T o t a l m u s c l e w a s c a l c u l a t e d o n 4 5 p e r c e n t o f b o d y w e i g h t ( S t a n d e t a l , 1 9 6 2 ) ^ T o t a l b o n e w a s c a l c u l a t e d a s 6 p e r c e n t o f b o d y w e i g h t ( S t a n d e t a l , 1 9 6 2 0 l i v t r • H e a r t * l u n g • K i d n o y l V H o o d | l o l o l | o • " 0 . . o ^X*u.__ T ims 0 i o v r i | F i g u r e 7 T o t a l O r g a n U p t a k e o f 1 0 - I o d o c a p r i c A c i d by L i v e r , H e a r t , L u n g , K i d n e y s and B l o o d i n M i c e 3 3 R a d i o a c t i v i t y l e v e l s h a v e been d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . 91 p r o c e s s o c c u r s r a p i d l y , h e n c e t h e e s t i m a t e d m y o c a r d i a l h a l f - t i m e o f 123 I - h e x a d e c e n o i c a c i d i s l e s s t h a n 2 5 m i n u t e s ( P o e e t a l . , 1 9 7 6 a ) . I o d o a c e t a t e , t h e m e t a b o l i c e n d p r o d u c t , i s s u b j e c t e d t o h y d r o l y s i s , t h u s r e l e a s i n g t h e i o d i n e - l a b e l w h i c h d i f f u s e d f r o m t h e m y o c a r d i u m , t o t h e b l o o d s t r e a m ( R o b i n s o n a n d L e e , 1 9 7 5 ) . Poe e t a l . ( 1 9 7 5 a ) o b t a i n e d s i m i l a r r e s u l t s o f m y o c a r d i a l 131 c l e a r a n c e a f t e r i n t r a c o r o n a r y i n j e c t i o n s o f I - h e x a d e c e n o i c a c i d a n d 131 I - o l e i c a c i d i n d o g s . A b i p h a s i c m y o c a r d i a l c l e a r a n c e c u r v e was o b t a i n e d f o r e a c h r a d i o i o d i n a t e d f a t t y a c i d w i t h i n t h e f i r s t two m i n u t e s a f t e r i n j e c t i o n . A s s u m p t i o n s w e r e made t h a t t h e f i r s t p h a s e o f t h e c u r v e r e p r e s e n t e d a wash o u t o f n o n - e x t r a c t e d f a t t y a c i d , w h e r e a s t h e s e c o n d p h a s e r e p r e s e n t e d t h e f a t t y a c i d r e t a i n e d i n t h e h e a r t a n d m e t a b o l i z e d . S u b s e q u e n t l y , Poe e t a l . ( 1 9 7 6 a ) f o u n d t h a t t h e d i s a p p e a r a n c e o f 123 I - h e x a d e c e n o i c a c i d f r o m t h e m y o c a r d i u m a p p r o x i m a t e d a m o n o e x p o n e n t i a l f u n c t i o n , a l t h o u g h t h e r e was a s l i g h t l y s l o w e r c l e a r a n c e r a t e a f t e r 10 m i n u t e s . T h e s e r e s u l t s , h o w e v e r , w e r e o b t a i n e d u s i n g a d i f f e r e n t a n i m a l m o d e l , a d i f f e r e n t m e t h o d o f i n j e c t i o n , a s w e l l a s d i f f e r e n t r a d i o i o d i n a t e d f a t t y a c i d s . The t h i r d c o m p o n e n t p r o b a b l y r e p r e s e n t e d t h e r a d i o i o d i n a t e d f a t t y a c i d w h i c h was n o t o x i d i z e d by B e t a - o x i d a t i o n , b u t was p r e s u m a b l y i n c o r p o r a t e d i n t o i n t r a c e l l u l a r t r i g l y c e r i d e s o r o t h e r c o m p l e x l i p i d s w i t h i n t h e m y o c a r d i u m , t h u s a c c o u n t i n g f o r t h e a p p a r e n t s t e a d y s t a t e ( E v a n s e t a l . , 1 9 6 3 a ) . I n e a r l i e r s t u d i e s , i t was d e m o n s t r a t e d t h a t o v e r 2 / 3 o f t h e r a d i o a c t i v i t y p r e s e n t i n t h e h e a r t 4 h o u r s a f t e r 131 i n j e c t i o n o f I - o l e i c a c i d was i n t h e t r i g l y c e r i d e f o r m ( E v a n s e t a l . , 1 9 6 5 ) . 92 A s i m i l a r p a t t e r n was o b s e r v e d f o r t h e o t h e r o r g a n s w i t h t h e e x c e p t i o n o f t h e s t o m a c h a n d t h e k i d n e y s ( T a b l e 7 , F i g u r e 7 ) . The h i g h e s t 131 I - c a p r i c a c i d a c c u m u l a t i o n was i n t h e m u s c l e , f o l l o w e d b y t h e b l o o d , b o n e , i n t e s t i n e s , l i v e r , k i d n e y , h e a r t , l u n g , s t o m a c h a n d s p l e e n . When t h e r e s u l t s a r e e x p r e s s e d i n t h i s m a n n e r , no o r g a n a p p e a r s t o h a v e a n y 131 s p e c i a l a f f i n i t y t o i n c o r p o r a t e I - c a p r i c a c i d . T h i s was e v i d e n t b y t h e r a p i d d e c r e a s e o f r a d i o a c t i v i t y w i t h i n e a c h o r g a n d u r i n g t h e f i r s t h o u r . The h i g h a c c u m u l a t i o n o f r a d i o a c t i v i t y i n t h e m u s c l e a n d t h e b l o o d was due t o t h e l a r g e t o t a l mass o r v o l u m e i n c o n s i d e r a t i o n . 131 The b l o o d l e v e l r e f l e c t e d a r a p i d c l e a r a n c e o f t h e I - c a p r i c a c i d w i t h l i t t l e r e s i d u a l a c t i v i t y r e m a i n i n g a t 24 h o u r s . H o w e v e r , t h e r e s u l t s t e n d e d t o f l u c t u a t e somewhat a l t h o u g h a s t e a d y d e c r e a s e o f r a d i o a c t i v i t y was s e e n . T h i s f l u c t u a t i o n c o u l d c o n c e i v a b l y be due t o t h e i o d i d e - 1 3 1 i o n d i f f u s i n g i n t o a n d o u t o f v a r i o u s t i s s u e s . C o m p a r t m e n t a l a n a l y s i s o f t h e b l o o d c o n c e n t r a t i o n w i t h t i m e was n o t a t t e m p t e d a l t h o u g h i t h a s b e e n r e p o r t e d i n t h e l i t e r a t u r e ( E v a n s e t a l . , 1 9 6 5 ; Poe e t a l . , 1 9 7 6 a ) . A b i p h a s i c d e c r e a s e i n b l o o d r a d i o a c t i v i t y was f o u n d by E v a n s e t a l . ( 1 9 6 5 ) a f t e r i n t r a v e n o u s ' - . 131 a d m i n i s t r a t i o n o f I - o l e i c a c i d . The i n i t i a l p h a s e was r a p i d , w i t h i n t h e f i r s t 10 m i n u t e s , f o l l o w e d by a s e c o n d , s l o w e r p h a s e . P a r t i t i o n o f t h e b l o o d i n t o l i p i d b o u n d a n d w a t e r s o l u b l e r a d i o a c t i v i t y i n d i c a t e d t h a t t h e i n i t i a l r a p i d p h a s e was due t o t h e d i s a p p e a r a n c e o f t h e 131 I - o l e i c a c i d w i t h a h a l f - l i f e o f a b o u t o n e a n d o n e - h a l f m i n u t e s . The r e m a i n i n g r a d i o a c t i v i t y i n t h e b l o o d was d e r i v e d f r o m " f r e e " r r a d i o i o d i n e p r e s e n t i n t h e o r i g i n a l i n j e c t i o n a n d f r o m r a d i o i o d i n e r e l e a s e d b y t h e 93 m e t a b o l i s m o f f a t t y a c i d i n t i s s u e s . The c l e a r a n c e o f t h e r a d i o i o d i n a t e d f a t t y a c i d f r o m b l o o d was v i r t u a l l y c o m p l e t e i n 20 m i n u t e s . A d d i t i o n a l b l o o d c l e a r a n c e r e s u l t s w e r e o b t a i n e d by Poe e t a l . ( 1 9 7 6 a ) u s i n g s e r i a l v e n o u s s a m p l i n g o f m o n g r e l > d o g s . A g a i n , a b i p h a s i c c l e a r a n c e p a t t e r n was s e e n . H a l f - t i m e v a l u e s f o r t h e f i r s t 123 p h a s e w e r e e x t r e m e l y r a p i d , 1 . 7 m i n u t e s f o r I - h e x a d e c e n o i c a c i d a n d 2 . 2 m i n u t e s f o r ^ C - o l e i c a c i d . A n a l y s i s o f t h e b l o o d a t 10 m i n u t e s a f t e r i n j e c t i o n s h o w e d t h a t o v e r 75% o f t h e a c t i v i t y was a t t r i b u t e d t o f r e e i o d i d e , w h i c h p r e s u m a b l y r e s u l t e d f r o m c o m p l e t e m e t a b o l i s m o f t h e l a b e l e d f a t t y a c i d , w i t h h y d r o l y s i s o f t h e t e r m i n a l i o d i n e a t o m ( P o e e t a l . , 1 9 7 6 a ) . The b o u n d c o m p o n e n t was a m i x t u r e o f r e s i d u a l l a b e l e d h e x a -d e c e n o i c a c i d , i o d i n a t e d b r e a k d o w n p r o d u c t s , a n d r e l e a s e d i o d i n e b o u n d t o p r o t e i n s . R e c e n t s t u d i e s by M a c h u l l a e t a l . ( 1 9 7 8 ) d e t e r m i n e d t h e f r e e b l o o d I o d i n e - 1 2 3 a f t e r a d m i n i s t r a t i o n o f l a b e l e d f a t t y a c i d i n t o m i c e u s i n g h i g h p r e s s u r e l i q u i d c h r o m a t o g r a p h y . T h e y f o u n d t h a t a t 1 m i n u t e a f t e r i n j e c t i o n , 100% o f t h e t o t a l b l o o d a c t i v i t y e x i s t e d a s t h e f r e e h a l i d e . The m i c e 'were s a c r i f i c e d b e t w e e n 15 s e c o n d s t o 10 m i n u t e s a f t e r i n j e c t i o n . I t a p p e a r s q u e s t i o n a b l e a s t o how p r e c i s e l y t i m e d t h e s e e x p e r i m e n t s w e r e a s i t w o u l d be v e r y d i f f i c u l t t o i n j e c t a n d s a c r i f i c e a mouse w i t h i n 15 s e c o n d s o f i n j e c t i o n . 131 The r e n a l c o n c e n t r a t i o n o f t h e I - c a p r i c a c i d a l s o f l u c t u a t e d . T h i s was e x p e c t e d s i n c e t h e k i d n e y s a r e t h e m a j o r r o u t e o f e l i m i n a t i o n o f t h e I o d i d e - 1 3 1 a n d a s t h e i o d i d e was f i l t e r e d , a p o r t i o n o f i t w o u l d be r e a b s o r b e d , a n d t h e r e m a i n d e r w o u l d e n t e r t h e 94 b l a d d e r a n d be v o i d e d ( M y a n t e t a l . , 1 9 5 0 ) . The i n i t i a l c o n c e n t r a t i o n o f r a d i o a c t i v i t y i n t h e s t o m a c h was 131 l o w , b u t i n c r e a s e d w i t h t i m e a s m e t a b o l i s m o f t h e I - c a p r i c a c i d a n d s u b s e q u e n t h y d r o l y s i s r e l e a s e d f r e e i o d i d e - 1 3 1 i n t o t h e b l o o d s t r e a m ( P o e e t a l . , 1 9 7 6 a ; M y a n t e t a l . , 1 9 5 0 ; N e l s o n e t a l . , 1 9 4 7 ) . The 131 g a s t r i c c o n c e n t r a t i o n o f t h e I - c a p r i c a c i d i n c r e a s e d g r a d u a l l y t o a maximum b e t w e e n . 5 h o u r and 1 h o u r , a f t e r w h i c h t h e c o n c e n t r a t i o n d e c r e a s e d . The c o n c e n t r a t i o n o f r a d i o a c t i v i t y i n t h e s t o m a c h was shown by E v a n s e t a l . ( 1 9 6 5 ) t o be due t o t h e r a p i d e x c r e t i o n o f r a d i o i o d i d e v f r o m t h e b l o o d by t h e g a s t r i c m u c o s a . The l a r g e a n d t h e s m a l l i n t e s t i n e a c t i v i t y d e c r e a s e d f r o m a maximum o f 2 . 9 5 % a t . 0 1 7 h o u r t o . 0 6 % a t 12 h o u r s . T h i s i n d i c a t e d 131 t h a t o n l y s m a l l q u a n t i t i e s o f t h e I - c a p r i c a c i d was e l i m i n a t e d v i a t h e f e c e s i n t h e t i m e p e r i o d s u n d e r o b s e r v a t i o n . T h i s i s i n a g r e e m e n t w i t h o u r f i n d i n g s s i n c e i t a p p e a r s t h a t d e g r a d a t i o n a n d s u b s e q u e n t h y d r o l y s i s r e l e a s e d f r e e I o d i d e - 1 3 1 i n t o t h e b l o o d s t r e a m , a n d i t was t h e f r e e I o d i d e - 1 3 1 w h i c h was e x c r e t e d v i a t h e u r i n e . I t h a s b e e n shown t h a t t h e i o d i d e i o n i s s o e f f i c i e n t l y a b s o r b e d by t h e i n t e s t i n e s t h a t o n l y m i n u t e t r a c e s o f i o d i d e e s c a p e d f r o m t h e b o d y i n t h e f e c e s ( N e l s o n e t a l . , 1 9 4 7 ) . 1 31 The I - c a p r i c a c i d was r a p i d l y c l e a r e d by t h e o r g a n s u n d e r i n v e s t i g a t i o n . By 24 h o u r s a f t e r i n j e c t i o n , o n l y t h e m u s c l e had g r e a t e r t h a n one p e r c e n t o f t h e i n j e c t e d d o s e r e m a i n i n g . I n v i e w o f t h e d i f f e r e n t s h a p e s a n d s i z e s o f t h e o r g a n s u n d e r 131 c o n s i d e r a t i o n , r e l a t i v e a c c u m u l a t i o n o f t h e I - c a p r i c a c i d was 95 e x p r e s s e d a s " p e r c e n t i n j e c t e d d o s e p e r g r a m o f o r g a n " . T h i s i s shown i n T a b l e 8 a n d F i g u r e 8 . The h e a r t s h o w e d t h e h i g h e s t c o n c e n t r a t i o n 131 o f I - c a p r i c a c i d i n i t i a l l y f o r t h e f i r s t . 0 5 h o u r s a f t e r i n j e c t i o n . The c o n c e n t r a t i o n t h e n d e c r e a s e d r a p i d l y u n t i l a b o u t . 1 6 7 h o u r s , a t w h i c h t i m e t h e c o n c e n t r a t i o n i n t h e b l o o d , t h e k i d n e y s , a n d t h e l u n g s w e r e h i g h e r t h a n t h a t o f t h e h e a r t . A f t e r . 1 6 7 h o u r s , t h e d e c r e a s e 131 i n r a d i o a c t i v i t y a p p e a r e d s l o w e r . The maximum c o n c e n t r a t i o n o f I -c a p r i c a c i d by t h e h e a r t was o b s e r v e d a t 1 m i n u t e a f t e r i n j e c t i o n , a t w h i c h t i m e t h e c o n c e n t r a t i o n was 9 . 2 5 % o f t h e i n j e c t e d d o s e p e r g r a m o f m y o c a r d i a l t i s s u e . M a c h u l l a e t a l . ( 1 9 7 8 ) m e a s u r e d t h e r a d i o a c t i v i t y i n mouse h e a r t s a f t e r i n t r a v e n o u s i n j e c t i o n s o f v a r i o u s l a b e l e d f a t t y 123 a c i d s . T h e y f o u n d t h e h i g h e s t m y o c a r d i a l a c c u m u l a t i o n o f I - h e p t a d e c a n o i c a c i d t o be 36% o f t h e i n j e c t e d d o s e p e r g r a m o f m y o c a r d i a l t i s s u e a t 30 s e c o n d s a f t e r i n j e c t i o n . T h i s v a l u e a p p e a r e d t o be s o m e w h a t ' ; h - i g h c o m p a r e d t o o u r r e s u l t s a s w e l l a s t h o s e r e p o r t e d by o t h e r i n v e s t i g a t o r s . I n o u r r e s u l t s , a t 5 m i n u t e s a f t e r i n j e c t i o n , 4 . 7 3 % o f t h e i n j e c t e d d o s e was c o n c e n t r a t e d i n e a c h gram o f m y o c a r d i u m . I n s i m i l a r e x p e r i m e n t s c a r r i e d o u t i n r a t s by B e i e r w a l t e s e t a l . ( 1 9 7 5 ) , t h e 131 c o n c e n t r a t i o n o f I - o l e i c a c i d i n t h e h e a r t a t 5 m i n u t e s was f o u n d t o be 1 . 7 8 % o ' f t h e i n j e c t e d d o s e p e r g r a m o f t i s s u e . T h i s l o w e r m y o c a r d i a l c o n c e n t r a t i o n c o u l d be a t t r i b u t e d t o s t e a r i c h i n d r a n c e due t o t h e b u l k y i o d i n e , as p r e v i o u s l y d i s c u s s e d . I n t h e same e x p e r i m e n t , t h e c o n c e n -14 t r a t i o n o f G - o l e i c a c i d was f o u n d t o be 3 . 4 2 % o f t h e i n j e c t e d , d o s e p e r g r a m o f m y o c a r d i u m , w h i c h was c o m p a r a b l e t o t h e r e s u l t s we o b t a i n e d . 131 H o w e v e r , t h e d e c r e a s e i n t h e m y o c a r d i a l c o n c e n t r a t i o n o f I - c a p r i c T A B L E V I I I R e l a t i v e O r g a n U p t a k e o f U l I - c a p r i c A c i d i n M i c e a , b T i m e ( h o u r s ) S p l e e n S t o m a c h I n t e s t i n e s M u s c l e . 0 1 7 1 . 5 6 ± . 1 4 2 . 8 0 ± . 4 3 1 . 7 3 + . 0 6 1 . 2 2 + . 1 6 1 . 6 7 ± . 1 4 . 0 3 3 2 . 0 0 ± . 1 1 3 . 6 2 ± . 5 4 1 . 6 8 ± . 0 4 1 . 2 4 ± . 0 6 1 . 7 8 ± . 0 8 . 0 5 0 2 . 1 2 + . 1 7 5 . 2 3 ± . 6 1 1 . 6 9 ± . 0 4 1 . 2 1 ± . 0 4 2 . 0 0 ± . 0 5 . 0 6 7 2 . 0 4 ± . 0 6 4 . 4 1 ± . 3 5 1 . 5 7 ± . 0 4 1 . 2 7 ± . 0 8 1 . 8 5 ± . 0 5 . 0 8 3 2 . 2 5 ± . 1 0 5 . 2 3 ± . 6 6 1 . 6 9 + . 0 9 1 . 4 4 ± . 0 6 2 . 2 2 + . 1 1 . 1 0 0 1 . 9 9 ± . 0 4 6 . 5 7 ± . 6 4 1 . 5 7 ± . 0 5 1 . 2 4 ± . 0 4 2 . 1 0 ± . 0 9 . 1 3 3 2 . 1 0 ± . 0 8 9 . 2 3 ± . 9 9 1 . 4 9 ± . 0 3 1 . 0 7 ± . 0 4 1 . 9 2 ± . 0 8 . 1 6 7 1 . 9 0 ± . 1 0 1 0 . 4 5 ± 1 . 8 2 1 . 4 2 ± . 0 9 . 9 0 ± . 0 5 1 . 7 6 ± . 1 9 . 2 5 0 1 . 8 3 ± . 1 4 1 0 . 0 5 ± 1 . 2 0 1 . 5 U . 1 2 • 9 3 ± . 0 5 1 . 5 5 ± . 0 6 . 3 3 3 1 . 5 9 ± . 1 1 8 . 1 2 + . 6 8 1 . 2 9 + . 0 3 . 9 0 ± . 0 5 1 . 5 3 ± . 0 6 . 4 1 7 1 . 6 4 ± . 0 8 1 1 . 8 2 ± . 8 2 1 . 2 9 ± . 0 6 . 9 2 ± . 0 4 1 . 4 5 ± . 1 2 . 5 0 0 1 . 4 3 ± . 0 9 1 3 . 5 6 ± . 7 9 1 . 1 0 + . 0 5 . 8 0 ± . 0 5 1 . 2 1 ± . 0 7 . 6 6 7 1 . 3 9 + . . 0 7 1 3 . 2 7 ± 2 . 1 3 1 . 0 6 + . 1 1 . 6 8 ± . 0 5 1 . 2 4 ± . 0 7 . 8 3 3 1 . 1 7 ± . 1 4 1 1 . 9 3 + . 8 6 . 9 0 ± . 0 8 . 5 8 ± . 0 5 1 . 8 1 ± . 0 8 1 . 0 0 1 . 4 1 ± . 5 9 1 2 . 5 6 ± 4 . 2 . 8 0 + . 1 1 . 4 1 ± . 0 8 . 8 9 * . 1 5 2 . 0 0 . 6 9 ± . 1 0 7 . 3 1 ± 1 . 4 . 5 3 ± . 0 7 . 4 3 ± . 0 3 . 6 0 ± . 0 5 4 . 0 0 . 3 5 ± . 0 5 4 . 2 6 + . 9 6 . 3 3 ± . 0 5 . 2 2 ± . 0 4 . 3 4 ± . 0 5 6 . 0 0 . 0 6 0 ± . 0 8 4 . 7 + 1 . 0 . 3 8 + . 0 7 . 2 3 ± . 0 3 . 3 7 ± . 0 7 1 2 . 0 0 . 0 5 0 ± . 0 0 . 2 3 ± . 0 6 . 0 4 + . 0 1 . 1 0 ± . 0 1 . 0 6 ± . 0 0 2 4 . 0 0 . 0 3 6 + . 0 1 . 1 5 ± . 0 3 . 0 2 9 + . 0 0 . 1 0 ± . 0 1 . 0 5 3 + . 0 0 3 E x p r e s s e d a s p e r c e n t o f i n j e c t e d 1 3 1 I - c a p r i c a c i d p e r g m o r g a n w e i g h t b M e a n v a l u e f r o m f i v e m i c e ± s t a n d a r d e r r o r o f t h e m e a n v B l o o d 0 l i v a r • M a o r i A l u n g • K i d n a y i O D T i m * ( h o u n ) F i g u r e 8 R e l a t i v e U p t a k e of 1 0 - I o d o c a p r i c A c i d by L i v e r , H e a r t , L u n g , K i d n e y s , a n d B l o o d i n M i c e a a R a d i o a c t i v i t y l e v e l s h a v e been d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . 9 8 a c i d was c o m p a r a t i v e l y f a s t e r t h a n t h a t o b s e r v e d by B e i e r w a l t e s e t a l . 131 131 ( 1 9 7 5 ) f o r I - o l e i c a c i d . T h i s c o u l d be due t o t h e f a c t t h a t I - c a p r i c a c i d i s a medium c h a i n l e n g t h f a t t y a c i d , a n d t h e r e f o r e an a c t i v a t i o n s t e p i s n o t n e c e s s a r y i n o r d e r f o r i t t o c r o s s t h e i n n e r m i t o c h o n d r i a l 1 membrane i n o r d e r t o be o x i d i z e d , w h e r e a s I - o l e i c a c i d > a l o n g c h a i n f a t t y a c i d , w o u l d r e q u i r e a c t i v a t i o n p r i o r t o m e t a b o l i s m . I n a d d i t i o n , 131 i n I - o l e i c a c i d , t h e i o d i n e g r o u p may c o n c e i v a b l y s l o w down t h e B e t a o x i d a t i o n c y c l e , t h u s a c c o u n t i n g f o r t h e s l o w e r c l e a r a n c e w i t h t i m e . The same t r e n d i n t h e d e c r e a s e o f r a d i o a c t i v i t y f r o m t h e l i v e r , t h e l u n g s , a n d t h e k i d n e y s was o b s e r v e d f r o m o u r e x p e r i m e n t a l r e s u l t s a s t h o s e r e p o r t e d by B e i e r w a l t e s e t a l . ( 1 9 7 5 ) . The s p l e e n , t h e i n t e s t i n e s , t h e m u s c l e , a n d t h e b o n e a l l d e m o n s t r a t e d s i m i l a r c o n c e n t r a t i o n s o f r a d i o a c t i v i t y a c c o m p a n i e d by s i m i l a r d e c r e a s e s w i t h t i me. To f u r t h e r i n v e s t i g a t e an o p t i m u m s c a n t i m e , t h e " p e r c e n t i n j e c t e d d o s e p e r g r a m o r g a n / p e r c e n t i n j e c t e d d o s e p e r ml b l o o d " was a l s o c a l c u l a t e d . T h i s d a t a i s p r e s e n t e d i n T a b l e 9 a n d F i g u r e 9 . The h i g h e s t o r g a n / b l o o d r a t i o f o r t h e h e a r t was f o u n d a t 2 m i n u t e s a f t e r i n j e c t i o n , a t w h i c h t i m e t h e c o n c e n t r a t i o n i n t h e l i v e r a n d l u n g s w a s / 131 c o n s i d e r a b l y l o w e r . The o p t i m a l s c a n t i m e f o r I - c a p r i c a c i d t h e r e -f o r e a p p e a r e d t o be i m m e d i a t e l y f o l l o w i n g i n j e c t i o n . The s u b j e c t s h o u l d be p o s i t i o n e d u n d e r t h e c a m e r a s o t h a t t h e s c a n c o u l d be s t a r t e d i m m e d i a t e l y a f t e r t h e i n j e c t i o n o f t h e r a d i o p h a r m a c e u t i c a l . The m a x i m a l o r g a n / b l o o d r a t i o o b t a i n e d f o r t h e h e a r t was 1 . 4 0 : 1 . T h i s was c o n s i d e r a b l y l o w e r ' . t h a n t h e 9 . 4 0 : 1 r a t i o r e p o r t e d T A B L E I X O r g a n / b l o o d D i s t r i b u t i o n o f 1 3 1 I - C a p r i c A c i d i n M i c e a , b T i m e ( h o u r s ) S p l e e n S t o m a c h I n t e s t i n e s M u s c l e B o n e B l o o d B l o o d B l o o d B l o o d B l o o d . 0 1 6 .23±.02 . 4 1 * . 0 7 . 2 5 ± . 0 1 . 1 8 ± . 0 3 . 2 5 1.02 . 0 3 3 .38±.02 . 6 3 ± . 0 9 . 2 9 ± . 0 1 .221.01 .3U . 0 1 . 0 5 0 .351.02 . 8 5 ± . 1 0 . 2 8 ± . 0 0 . 2 0 1 . 0 1 .331.01 . 0 6 7 .39± . 0 1 . 8 4 ± . 0 6 . 3 0 ± . 0 1 .241.01 .361.01 . 0 8 3 .38±.02 .891 . 1 4 .281.01 .241.01 .371.01 . 1 0 0 .391.01 1 . 2 8 ± . 1 3 • 3 1 + . 0 1 . 2 4 1 . 0 1 . 4 1 1 . 0 1 . 1 3 3 . 4 4 ± . 0 1 1.97± . 2 5 . 3 2 ± . 0 1 .231.02 . 4 0 1 . 0 1 . 1 6 7 .47± . 0 4 2 . 5 5 ± .39 .35± . 0 1 .221.00 .431.03 . 2 5 0 . 4 8 ± . 0 1 2 . 7 0 ± . 3 6 .40±.02 . 2 5 1.02 . 4 2 1.02 . 3 3 0 .43±.02 2 . 3 3 ± . 2 7 .37± . 0 1 . 2 6 1.02 .441.02 . 4 1 7 .46±.02 3 . 3 2 ± . 2 4 . 3 6 ± . 0 1 . 2 6 1.02 . 4 0 1 . 0 1 . 5 0 0 . 5 0 ± . 0 3 4 . 7 2 ± . 2 9 . 3 8 ± . 0 1 .281.01 . 4 2 1 . 0 1 . 6 6 7 . 5 0 1 . 0 3 4.59± . 4 8 .371.02 . 2 4 1 . 0 1 .441.02 . 8 3 3 . 5 0 ± . 0 3 5.20± . 3 8 .39± . 0 1 .251.01 .441.01 1 . 0 0 0 .651.18 5 . 8 1 H . 2 3 .4U.02 . 2 7 1 . 0 0 .451.01 2 . 0 0 0 .52±.02 5 . 3 6 ± . 4 8 .39± . 0 1 .341.03 .461.02 4 . 0 0 0 . 5 2 ± . 0 4 6 . 0 7 ± . 9 9 .47± . 0 4 . 3 1 1 . 0 3 . 5 0 1 . 0 4 6 . 0 0 0 .50±.02 5 . 6 5 ± . 5 6 .451.02 . 3 0 1 . 0 5 .441.01 1 2 . 0 0 0 . 8 0 ± . 1 5 3.59± . 3 0 . 6 U . 0 7 1 . 9 1 1 . 5 8 1 . 1 9 1 . 3 1 2 4 . 0 0 0 . 7 0 ± . 0 7 2.75± . 4 1 .57± . 0 4 2 . 0 5 1 . 1 0 1 . 0 7 1 . 1 2 a E x p r e s s e d a s r a t i o o f p e r c e n t i n j e c t e d d o s e p e r g m . o f o r g a n t o i n j e c t e d d o s e p e r m l . o f b l o o d . b M e a n v a l u e s f r o m f i v e m i c e i s t a n d a r d e r r o r o f t h e m e a n . o o F i g u r e 9 O r g a n / B l o o d D i s t r i b u t i o n o f 1 0 - I o d o c a p r i c A c i d by L i v e r , H e a r t , L u n g , a n d K i d n e y s i n M i c e a a R a d i o a c t i v i t y l e v e l s h a v e b e e n d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . 101 f o r I - o l e i c a c i d by E v a n s e t a l . ( 1 9 6 5 , 1 9 6 2 ) . H o w e v e r , t h e r e s u l t s o f E v a n s e t a l . ( 1 9 6 5 ) w e r e o b t a i n e d f r o m d o g s a n d t h e a d m i n i s t r a t i o n o f t h e 131 I - o l e i c a c i d was a c c o m p a n i e d by i n t r a v e n o u s i n f u s i o n s o f g l u c o s e a n d i n s u l i n . I t has b e e n o b s e r v e d t h a t i n s u l i n a n d g l u c o s e b o t h p r o m o t e d m y o c a r d i a l s t o r a g e o f f a t t y a c i d s d e r i v e d f r o m t h e c i r c u l a t i o n a n d d e c r e a s e d o x i d a t i o n o f t h e f a t t y a c i d s i n a l l b o d y t i s s u e s ( E v a n s e t a l . , 1 9 6 5 ) . I n t h e s t u d i e s o f S c h e l b e r t e t a l . ( 1 9 7 4 ) m y o c a r d i u m / b l o o d r a t i o s w e r e c a l c u l a t e d f o r r a t s i n j e c t e d w i t h r a d i o n u c l i d e s s u c h as 131 I - o l e i c a c i d . The h i g h e s t m y o c a r d i a l / b l o o d l e v e l was f o u n d a t 10 m i n u t e s a f t e r i n j e c t i o n , a n d was f o u n d t o be 2 . 4 0 : 1 . H o w e v e r , t h e s e r e s u l t s w e r e o b t a i n e d u s i n g d i f f e r e n t m e t h o d o l o g y f o r t h e l a b e l i n g p r o c e s s , d i f f e r e n t a n i m a l s , a n d a d i f f e r e n t v e i n f o r i n j e c t i o n . T h e s e f a c t o r s may h a v e a f f e c t e d t h e r e s u l t s . T h e r e a p p e a r s t o be an i n v e r s e r e l a t i o n s h i p b e t w e e n t h e d o s e o f r i o d o f a t t y a c i d a d m i n i s t e r e d a n d t h e m y o c a r d i u m / b l o o d r a t i o , ( S c h e l b e r t e t a l . , 1 9 7 4 ) . R a t i o s o f l e s s t h a n one w e r e o b s e r v e d w i t h d o s e s as h i g h as 8mg/Kg body w e i g h t w h i l e a r a t i o o f 6 . 7 : 1 was o b s e r v e d u s i n g . 7 6 mg/Kg H i g h s p e c i f i c - a c t i v i t y f a t t y a c i d s a p p e a r e d t o p r o v i d e h i g h e r m y o c a r d i u m / b l o o d r a t i o s . The d o s e o f t h e t o t a l f a t t y a c i d u s e d i n o u r e x p e r i m e n t s was a p p r o x i m a t e l y 2 . 6 7 m g / K g . H o w e v e r , t h i s i n c l u d e d t h e u n l a b e l e d L i b r o m o c a p r i c a c i d as w e l l . A l t h o u g h t h e u n l a b e l e d b r o m o c a p r i c a c i d was n o t d e t e c t e d d u r i n g gamma c o u n t i n g o f t h e s a m p l e s , i t may h a v e i n f l u e n c e d t h e m y o c a r d i u m / b l o o d r a t i o . 102 b) I J I I - L a u r i c A c i d 131 The r e s u l t s o f t h e o r g a n d i s t r i b u t i o n s t u d i e s f o r I - l a u r i c a c i d , e x p r e s s e d as " p e r c e n t i n j e c t e d d o s e p e r t o t a l o r g a n " a r e p r e s e n t e d i n T a b l e 10 and F i g u r e 1 0 . A g a i n , a g e n e r a l t r e n d was o b s e r v e d t h a t t h e c o n c e n t r a t i o n o f t h e r a d i o p h a r m a c e u t i c a l was t h e h i g h e s t i m m e d i a t e l y f o l l o w i n g i n j e c t i o n , a f t e r w h i c h t h e r e was a d e c l i n e o f r a d i o a c t i v i t y w i t h t i m e . 131 The h i g h e s t m y o c a r d i a l u p t a k e o f I - l a u r i c a c i d was w i t h i n o n e m i n u t e a f t e r i n j e c t i o n . The d e c r e a s e i n r a d i o a c t i v i t y w i t h t i m e w i t h i n t h e m y o c a r d i u m was a g a i n o b s e r v e d t o o c c u r i n an e x p o n e n t i a l m a n n e r , b e i n g 131 131 s i m i l a r t o t h a t o f I - c a p r i c a c i d . I t c a n be a s s u m e d t h a t b o t h I - l a u r i c 131 a c i d and I - c a p r i c a c i d a r e c l e a r e d i n t h e same m a n n e r f r o m t h e h e a r t , s i n c e t h e f a t t y a c i d s d i f f e r e d o n l y by 2 c a r b o n u n i t s i n t h e h y d r o c a r b o n c h a i n . I n i t i a l m y o c a r d i a l e x t r a c t i o n p r e s u m a b l y a c c o u n t e d f o r t h e p e a k c o n c e n t r a t i o n i m m e d i a t e l y f o l l o w i n g i n j e c t i o n . S u b s e q u e n t l y , a p o r t i o n o f 131 t h e I - l a u r i c a c i d was p r o b a b l y m e t a b o l i z e d by B e t a o x i d a t i o n ( O l i v e r , 1 9 7 6 ; S p i t z e r a n d S p i t z e r , 1 9 7 1 ) . The f a t t y a c i d n o t m e t a b o l i z e d was p r e s u m a b l y i n c o r p o r a t e d i n t o t r i g l y c e r i d e s o r o t h e r p h o s p h o l i p i d s ( E v a n s e t a l . , 1 9 6 5 ) . 131 The I - l a u r i c a c i d u p t a k e by t h e m y o c a r d i u m a n d t h e l u n g s w e r e a l m o s t i d e n t i c a l , and t h e d e c l i n e o f t h e r a d i o a c t i v i t y w i t h t i m e was a l m o s t i n d i s t i n g u i s h a b l e . T h i s s u g g e s t e d t h a t t h e r e may h a v e b e e n no 131 s i g n i f i c a n t p r e f e r e n t i a l u p t a k e o f t h e I - l a u r i c a c i d by t h e m y o c a r d i u m , 131 o r t h a t t h e . I - l a u r i c a c i d was b e i n g r e t a i n e d by t h e l u n g s . T A B L E X T o t a l U p t a k e o f I J I I - L a u r i c A c i d b y t h e S p l e e n , S t o m a c h . I n t e s t i n e s , M u s c l e , a n d B o n e o f M i c e a ' T i m e ( h o u r s ) S p l e e n S t o m a c h I n t e s t i n e s M u s c l e 0 B o n e d - . 0 1 7 . 4 1 ± . 0 3 . 8 1 ± . 1 0 4 . 7 4 ± . l l 2 9 . 2 8 ± . 8 4 4 . 3 4 ± . 3 2 . 0 3 3 . 3 7 ± . 0 7 1 . 5 0 ± . 1 4 4 . 4 6 ± . 2 3 2 4 . 4 3 ± 1 . 1 7 4 . 2 7 ± . 2 8 . 0 5 0 . 3 1 ± . 0 2 1 . 2 5 + . 1 2 3 . 1 0 + . 1 0 1 7 . 5 4 ± 1 . 2 3 3 . 5 2 + . 2 1 . 0 6 7 . 3 7 ± . 0 2 1 . 5 4 + . 1 8 3 . 6 4 ± . 1 5 2 3 . 7 3 ± 1 . 1 5 4 . 5 9 + . 2 5 . 0 8 3 . 2 9 ± . 0 3 1 . 6 0 + . 1 8 2 . 7 7 ± . 2 3 1 6 . 5 6 + . 7 2 3 . 3 9 ± . 1 3 . 1 0 0 . 3 6 ± . 0 5 1 . 9 4 + . 1 5 3 . 9 1 + . 1 7 2 1 . 8 3 + 1 . 0 9 4 . 4 5 ± . 3 0 . 1 3 3 . 4 7 ± . 0 6 2 . 5 0 + . 3 6 4 . 0 0 + . 2 6 2 1 . 6 4 ± 1 . 4 7 4 . 3 9 ± . 2 8 . 1 6 7 . 2 8 ± . 0 2 2 . 6 4 + . 4 3 3 . 8 0 ± . 2 8 1 7 . 6 U . 8 6 3 . 5 8 ± . 1 7 . 2 5 0 . 3 4 ± . 0 3 3 . 8 2 ± . 4 9 3 . 0 2 ± . 1 9 1 5 . 3 8 ± . 6 3 3 . 2 4 + . 1 4 . 3 3 3 . 2 7 ± . 0 4 2 . 2 1 ± . 2 6 2 . 3 0 ± . 1 3 1 2 . 7 9 ± . 6 5 2 . 6 0 ± . 0 9 . 4 1 7 . 2 3 + . 0 3 2 . 0 8 ± . 3 3 2 . 0 8 ± . 1 4 1 1 . 5 7 ± . 8 8 2 . 3 9 ± . 1 7 . 5 0 0 . 2 4 ± . 0 2 4 . 0 5 ± . 9 5 2 . 3 H . 2 4 1 1 . 7 6 ± 1 . 1 7 2 . 4 3 ± . 1 7 . 6 6 7 . 1 9 + . 0 2 3 . 4 8 ± . 1 4 2 . 2 8 ± . 1 2 1 1 . 3 7 + 1 . 0 3 2 . 2 0 ± . l l . 8 3 3 . 2 1 + . 0 4 3 . 9 7 ± . 8 2 2 . 6 0 + . 3 9 1 1 . 8 6 ± 1 . 5 4 2 . 5 7 ± . 2 9 1 . 0 0 0 . 1 6 ± . 0 2 2 . 0 8 ± . 4 4 1 . 4 6 ± . 1 7 7 . 2 9 ± . 7 8 1 . 4 4 ± . 1 2 2 . 0 0 0 . 2 0 ± . 0 2 5 . 8 4 ± . 7 1 1 . 6 3 ± . 1 3 8 . 2 4 ± . 3 2 1 . 8 7 ± . 0 9 3 . 0 0 0 . 1 9 ± . 0 3 4 . 7 7 + 1 . 0 1 1 . 6 3 ± . 1 8 8 . 0 7 ± . 9 7 1 . 8 6 ± . 2 1 4 . 0 0 0 . 0 5 ± . 0 1 1 . 0 7 ± . 3 0 . 7 5 + . 1 4 5 . 0 2 ± 1 . 0 2 . 6 6 ± . 0 6 6 . 0 0 0 . 0 7 ± . 0 1 1 . 1 6 ± . 1 7 . 7 2 ± . 0 6 3 . 2 3 + . 3 9 . 7 H . 1 1 1 2 . 0 0 0 . 0 1 + . 0 0 1 . 0 6 ± . 0 0 4 . 1 8 ± . 0 1 2 . 5 6 ± . 4 5 . 3 5 ± . 0 4 2 4 . 0 0 0 • 0 2 ± . 0 0 1 . 0 8 ± . 0 2 . 1 U . 0 2 1 . 3 1 + . 6 4 . 3 5 ± . 0 6 a 1 ^1 E x p r e s s e d a s p e r c e n t o f I - l a u r i c a c i d p e r t o t a l o r g a n . ^ M e a n v a l u e s f o r f i v e m i c e ± s t a n d a r d e r r o r o f t h e m e a n c T o t a l m u s c l e w a s c a l c u l a t e d o n 4 5 p e r c e n t o f b o d y w e i g h t ( S t a n d e t a l . , 1 9 6 2 ) d T o t a l b o n e w a s c a l c u l a t e d a s 6 p e r c e n t o f b o d y w e i g h t ( S t a n d e t a l . , 1 9 6 2 ) F i g u r e 10 T o t a l O r g a n U p t a k e o f 1 2 - I o d o l a u r i c A c i d by L i v e r , H e a r t , L u n g , K i d n e y s , and B l o o d i n M i c e a R a d i o a c t i v i t y l e v e l s h a v e been d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . 105 The d e c l i n e o f t h e t o t a l b l o o d c o n c e n t r a t i o n o f I - l a u r i c a c i d a p p e a r e d t o be v e r y s p o r a d i c , w i t h p e a k s o c c u r i n g a t .1 h o u r s , . 5 h o u r s , a n d a t 2 - 3 h o u r s . A g a i n , a r a p i d b l o o d c l e a r a n c e o f t h e 131 131 • I - l a u r i c a c i d was n o t e d , as w i t h I - c a p r i c a c i d . H o w e v e r , t h e 1 3 1 t o t a l b l o o d c o n c e n t r a t i o n seemed t o f l u c t u a t e much more t h a n t h e I - c a p r i c a c i d . The h e p a t i c c o n c e n t r a t i o n o f 1 2 - i o d o l a u r i c . a c i d f l u c t u a t e d i n a m a n n e r p a r a l l e l t o t h a t o f t h e b l o o d , t h u s i m p l y i n g t h a t t h e c o n c e n t r a t i o n 131 i n t h e l i v e r was due t o d i f f u s i o n o f t h e I - l a u r i c a c i d r a t h e r t h a n by s e l e c t i v e r e t e n t i o n ( P e r l m a n e t a l . , 1 9 4 1 ) . The k i d n e y c o n c e n t r a t i o n was 131 a g a i n v a r i a b l e w i t h p e a k l e v e l s n o t e d a t 2 - 3 h o u r s . T h e I - l a u r i c a c i d was r a p i d l y c l e a r e d by t h e b l o o d a s w e l l as t h e s p l e e n , t h e i n t e s t i n e s , t h e m u s c l e , and t h e b o n e . The c o n c e n t r a t i o n o f r a d i o a c t i v i t y w i t h i n t h e s e o r g a n s w e r e l e s s t h a n 1% by 24 h o u r s a f t e r i n j e c t i o n . The c o n c e n t r a t i o n 131 o f I - l a u r i c . a c i d by t h e i n t e s t i n e s was . s o m e w h a t - h i g h e r t h a n t h e v a l u e 131 o b s e r v e d f o r I - c a p r i c a c i d , 4 . 7 4 % c o m p a r e d t o 2 . 9 5 % a t . 0 1 7 h o u r r e s p e c -t i v e l y . T h i s d i f f e r e n c e c o u l d p o s s i b l y be a t t r i b u t e d t o t h e p r e p a r a t i o n s 131 t h e m s e l v e s , s i n c e i t w o u l d a p p e a r t h a t t h e c o n c e n t r a t i o n o f t h e I - l a u r i c a c i d was h i g h e r i n t h e m u s c l e , t h e b o n e , as w e l l as t h e s p l e e n f o r t h e t i m e 131 i n t e r v a l s o b s e r v e d t h a n t h e I - c a p r i c a c i d . The u p t a k e by t h e s t o m a c h was h i g h e s t b e t w e e n 2 - 3 h o u r s a f t e r i n j e c t i o n , a l t h o u g h a p e a k l e v e l was a l s o n o t e d a t . 2 5 h o u r s a n d a t . 5 h o u r s . T h i s i s i n a g r e e m e n t w i t h t h e h y p o t h e s i s t h a t i t i s t h e f r e e I o d i d e - 1 3 1 w h i c h i s e x c r e t e d by t h e g a s t r i c m u c o s a ( N e l s o n e t a l . , 1 9 4 7 ) . The f r e e I o d i d e - 1 3 1 i s p r o b a b l y t h e r e s u l t o f h y d r o l y s i s o f i o d o a c e t a t e , t h e e n d p r o d u c t o f B e t a o x i d a t i o n o f t h e i o d o f a t t y a c i d ( R o b i n s o n and L e e , 1 9 7 5 ) . 106 I n T a b l e 11 a n d F i g u r e 1 1 , t h e r e s u l t s o f t h e " p e r c e n t i n j e c t e d d o s e p e r gram o f o r g a n " a r e s h o w n . The i n i t i a l u p t a k e a t 1 m i n u t e by t h e h e a r t was 1 3 . 2 % , c o m p a r e d t o 11% f o r t h e l i v e r . The o b s e r v e d d e c l i n e 131 . . . . , o f I - l a u r i c . a c i d p e r gram o f t i s s u e f o r t h e h e a r t , t h e l i v e r , t h e l u n g s , a n d t h e k i d n e y s was v e r y s i m i l a r . The v a l u e s w e r e c l u s t e r e d , f o l l o w i n g a g e n e r a l t r e n d w i t h t h e d e c l i n e o f r a d i o a c t i v i t y i n t h e b l o o d w i t h t i m e . I n v i e w o f t h e c l o s e a n a t o m i c a l p r o x i m i t y o f t h e s e o r g a n s , i t w o u l d be v e r y d i f f i c u l t t o c l e a r l y i d e n t i f y t h e m y o c a r d i u m o n a s c a n . The " p e r c e n t i n j e c t e d d o s e p e r g r a m o r g a n / p e r c e n t i n j e c t e d d o s e p e r ml . b l o o d " was a l s o c a l c u l a t e d . ( T a b l e 12 a n d F i g u r e 1 2 ) r , 131 The h e a r t h a d t h e h i g h e s t u p t a k e o f I - l a u r i c a c i d a t t h e commencement o f t h e s t u d i e s , f o l l o w e d by t h e l u n g , t h e l i v e r , and t h e k i d n e y s . H o w e v e r , t h e r e s u l t s w e r e v e r y s i m i l a r and a p p e a r e d t o be c l u s t e r e d . 131 T h e r e was a g e n e r a l d e c l i n e o f t h e I - l a u r i c a c i d w i t h t i m e , u n t i l 3 h o u r s p o s t - i n j e c t i o n . A f t e r 3 h o u r s , t h e o r g a n / b l o o d r a t i o s i n c r e a s e d a s t h e r a d i o a c t i v i t y was c l e a r e d f r o m t h e b l o o d . An e x c e p t i o n t o t h i s was t h e k i d n e y s , w h i c h showed a v e r y h i g h c o n c e n t r a t i o n o f r a d i o a c t i v i t y a t 2 - 3 h o u r s a f t e r i n j e c t i o n . The r e a s o n f o r t h i s i s n o t u n d e r s t o o d . The o r g a n / b l o o d r a t i o s f o r t h e s p l e e n , t h e i n t e s t i n e s , t h e m u s c l e , a n d t h e bone w e r e r e l a t i v e l y l o w a n d s h o w e d a n a l m o s t i d e n t i c a l i n c r e a s e " w i t h , t i m e - The h i g h e s t r a t i o s f o r t h e s p l e e n a n d s t o m a c h , h o w e v e r , o c c u r r e d a t 2 h o u r s a f t e r i n j e c t i o n . The o t h e r o r g a n s o r t i s s u e s s h o w e d a c o n t i n u e d i n c r e a s e i n o r g a n / b l o o d r a t i o s as t h e b l o o d was c l e a r e d o f t h e r a d i o a c t i v i t y . T A B L E X I R e l a t i v e O r g a n U p t a k e o f 1 3 1 1 - L a u r i e A c i d i n M i c e a , * > T i m e ( h o u r s ) S p l e e n S t o m a c h I n t e s t i n e s M u s c l e B o n e . 0 1 7 2 . 4 1 4 . 2 3 3 . 2 5 * . 3 5 2 . 6 7 4 . 1 1 2 . 1 6 + . 1 3 2 . 5 1 4 . 1 7 . 0 3 3 3 . 0 1 4 . 1 5 6 . 0 7 * . 4 1 2 . 4 6 4 . 2 1 2 . 0 7 + 1 2 2 . 7 2 4 . 2 2 . 0 5 0 2 . 2 3 ± . 0 8 5 . 0 2 ± . 6 5 1 . 8 0 4 . 0 6 1 . 3 7 4 . 1 0 2 . 1 7 4 . 1 1 . 0 6 7 2 . 9 1 4 . 1 1 5 . 8 5 ± . 7 3 2 . 1 8 4 . 0 8 1 . 8 4 4 . 1 7 2 . 6 5 4 . 2 0 . 0 8 3 2 . 1 7 ± . 1 0 5 . 0 2 4 . 8 2 1 . 6 7 4 . 0 5 1 . 3 9 4 . 0 6 2 . 1 3 4 . 0 7 . 1 0 0 2 . 7 0 4 . 1 0 6 . 9 7 4 . 5 2 1 . 9 5 4 . 1 1 1 . 6 0 4 . 1 0 2 . 4 5 4 . 2 2 . 1 3 3 2 . 6 2 4 . 1 0 9 . 1 3 4 1 . 1 0 1 . 8 9 4 . 0 7 1 . 6 0 4 . 0 9 2 . 4 5 4 . 1 4 . 1 6 7 2 . 3 1 4 . 1 7 9 . 3 2 4 1 . 9 4 1 . 7 2 4 . 1 4 1 . 3 8 4 . 1 0 2 . 1 0 4 . 1 6 . 2 5 0 2 . 1 9 ± . 1 9 1 2 . 9 9 4 . 8 4 1 . 4 8 4 . 0 8 1 . 1 6 4 . 0 5 1 . 8 3 4 . 0 9 . 3 3 3 1 . 7 2 + . 0 7 1 0 . 4 8 4 1 , . 3 3 1 . 3 8 4 . 0 3 1 . 0 6 4 . 0 4 1 . 6 2 4 . 0 7 . 4 1 7 1 . 4 5 + . 1 0 1 0 . 4 2 4 . . 9 4 1 . 1 4 4 . 0 6 1 . 1 4 4 . 0 7 1 . 4 7 4 . 1 2 . 5 0 0 1 . 5 8 4 . 1 4 1 4 . 2 9 4 2 . . 0 5 1 . 2 8 4 . 1 2 . 9 1 4 . 1 0 1 . 4 1 4 . 1 4 . 6 6 7 1 . 4 7 4 . 2 1 1 2 . 7 1 4 . . 3 5 1 . 1 2 4 . 0 7 - . 8 9 4 . 0 9 1 . 2 9 4 . 0 5 . 8 3 3 1 . 5 8 4 . 1 9 1 4 . 4 0 4 . . 2 5 1 . 1 8 + . 1 2 . 8 9 4 . 1 1 1 . 4 6 4 . 1 8 1 . 0 0 0 1 . 1 1 4 . 1 0 8 . 0 9 + 1 . 3 6 . 9 4 4 . 0 6 . 7 4 4 . 0 5 . 9 9 4 . 0 9 2 . 0 0 0 1 . 2 1 4 . 1 3 2 0 . 9 2 4 3 . . 2 1 . 9 2 4 . 1 0 . 6 2 4 . 0 3 1 . 0 6 4 . 0 5 3 . 0 0 0 1 . 1 5 4 . 1 4 1 6 . 2 8 4 2 . 2 7 . 8 5 4 . 1 2 . 5 8 4 . 0 8 1 . 0 1 4 . 1 2 4 . 0 0 0 . 3 4 4 . 0 6 4 . 3 H 1 . 4 7 . 4 8 4 . 1 2 . 4 2 4 . 0 8 . 5 8 4 . 1 6 6 . 0 0 0 . 4 0 ± . 0 6 4 . 1 1 4 . 5 6 . 3 8 4 . 0 4 . 2 4 4 . 0 2 . 4 0 4 . 0 6 1 2 . 0 0 0 . 0 7 9 + 0 1 . 2 4 4 . 0 2 . 0 8 4 . 0 1 . 1 9 4 . 0 3 . 2 0 4 . 0 2 2 4 . 0 0 0 . 1 2 4 . 0 1 . 3 0 + . 0 5 . 0 6 4 . 0 1 . 1 8 4 . 0 4 . 1 9 4 . 0 3 a E x p r e s s e d a s p e r c e n t o f I n j e c t e d 1 3 1 I - L a u r i c a c i d p e r g r a m o r g a n w e i g h t . b M e a n v a l u e f r o m f i v e m i c e + s t a n d a r d e r r o r o f t h e m e a n . I t.O 10 3 0 T i m * (howrt | F i g u r e 11 R e l a t i v e U p t a k e o f 1 2 - I o d o T a u r i c A c i d by L i v e r H e a r t , L u n g , K i d n e y s a n d B l o o d i n M i c e 3 a R a d i o a c t i v i t y l e v e l s h a v e b e e n d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . T A B L E X I I T i O r q a n / b l o o d 1 3 1 D i s t r i b u t i o n o f I - L a u r i c A c i d i n M i c e a , b i m e ( h o u r s ) S p l e e n B l o o d S t o m a c h B l o o d I n t e s t i n e s B l o o d M u s c l e B l o o d B o n e B l o o d . 0 1 6 . 2 3 ± . 0 3 . 3 1 1 . 0 3 . 2 6 1 . 0 1 . 2 U . 0 1 . 2 4 1 . 0 1 . 0 3 3 . 4 5 ± . 0 5 . 9 3 1 . 1 4 . 3 6 1 . 0 4 . 3 2 1 . 0 4 . 4 2 1 . 0 7 . 0 5 0 . 3 6 ± . 0 1 . 8 0 1 . 0 8 . 2 9 1 . 0 1 . 2 2 1 . 0 2 . 3 5 1 . 0 1 . 0 6 7 . 4 4 1 . 0 2 . 8 8 . 1 . 1 1 . 3 3 1 . 0 1 . 2 8 1 . 0 1 . 4 0 1 . 0 2 . 0 8 3 . 4 2 1 . 0 0 . 9 5 i . 1 1 . 3 2 1 . 0 1 . 2 7 1 . 0 2 . 4 1 1 . 0 1 . 1 0 0 . 4 9 1 . 0 4 1 . 2 6 1 . 1 4 . 3 5 1 . 0 1 . 2 9 1 . 0 2 . 4 4 1 . 7 5 . 1 3 3 . 5 0 1 . 0 2 1 . 7 3 1 . 1 7 . 3 6 1 . 0 2 . 3 1 1 . 0 2 . 4 8 1 . 0 3 . 1 6 7 . 4 3 1 . 0 3 1 . 7 0 i . 2 8 . 3 2 1 . 0 1 . 2 6 1 . 0 1 . 4 0 1 . 0 2 . 2 5 0 . 4 9 1 . 0 3 2 . 9 0 t . 1 6 . 3 3 1 . 0 1 . 2 6 1 . 0 2 . 4 U . 0 2 . 3 3 0 . 4 8 1 . 0 1 2 . 6 1 t : . 0 8 . 3 9 1 . 0 1 . 3 U . 0 2 . 4 6 1 . 0 2 . 4 1 7 . 5 4 1 . 0 2 4 . 0 0 1 . 4 9 . 4 3 1 . 0 2 . 3 6 1 . 0 3 . 5 5 1 . 0 4 . 5 0 0 . 4 9 1 . 0 2 4 . 3 6 1 . 4 6 . 4 0 1 . 0 1 . 2 8 1 . 0 2 . 5 U . 0 6 . 6 6 7 . 4 9 1 . 0 4 4 . 3 9 1 . 3 6 . 3 8 1 . 0 1 . 3 0 1 . 0 2 . 4 4 1 . 0 3 . 8 3 3 . 5 8 1 . 0 2 5 . 2 6 t . 7 8 . 4 4 1 . 0 2 . 3 3 1 . 0 1 . 5 4 1 . 0 3 1 . 0 0 0 . 5 5 1 . 0 3 4 . 1 4 1 . 8 0 . 4 8 1 . 0 4 . 3 4 1 . 0 4 . 5 0 1 . 0 4 2 . 0 0 0 . 6 0 1 . 0 5 1 0 . 3 1 1 . 9 5 . 4 6 1 . 0 3 . 3 2 1 . 0 3 . 5 4 1 . 0 4 3 . 0 0 0 . 5 8 1 . 0 3 8 . 5 7 1 1 . 3 8 . 4 3 ± . 0 2 . 3 0 1 . 0 2 . 5 3 1 . 0 1 4 . 0 0 0 . 4 6 1 . 1 2 5 . 1 2 H . 1 7 . 6 U . 0 8 . 5 4 1 . 0 7 . 7 3 1 . 1 3 6 . 0 0 0 . 5 5 1 . 0 6 5 . 7 2 1 . 5 9 . 5 3 ± . 0 3 . 3 4 1 . 0 2 . 5 6 1 . 0 8 1 2 . 0 0 0 . 5 5 1 . 0 4 1 . 7 2 1 . 0 5 . 5 8 1 . 0 3 1 . 3 7 1 . 1 9 1 . 4 6 1 . 2 3 2 4 . 0 0 0 1 . 6 4 1 . 1 8 3 . 9 3 1 . 6 9 . 8 6 1 . 1 8 2 . 5 4 1 . 7 4 2 . 6 6 1 . 6 1 a E x p r e s s e d a s a r a t i o o f p e r c e n t i n j e c t e d d o s e p e r g m o f o r g a n t o p e r c e n t i n j e c t e d d o s e p e r m l o f b l o o d . b M e a n v a l u e s f r o m f i v e m i c e i s t a n d a r d e r r o r o f t h e m e a n . 8 O liv«r « H.o.t * l u n g 2 0 -a • O )l I I 1 1 01 I 1.0 10 30 T i m * ( t iovr i f F i g u r e 12 O r g a n / B l o o d D i s t r i b u t i o n o f 12 - I o d o l a u r i c A c i d by L i v e r , H e a r t , L u n g a n d K i d n e y s i n M i c e 3 a R a d i o a c t i v i t y l e v e l s have been d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . I l l I n r e v i e w i n g t h e s e r e s u l t s , i t d o e s n o t a p p e a r t h a t 1 2 - i o d o l a u r i c a c i d w o u l d be an i d e a l m y o c a r d i a l s c a n n i n g a g e n t , a l t h o u g h t h e i n i t i a l u p t a k e b y t h e m y o c a r d i u m may a l l o w v i s u a l i z a t i o n . I t w o u l d a p p e a r q u e s t i o n a b l e i f t h e h e a r t c o u l d be d i f f e r e n t i a t e d f r o m t h e l u n g s a n d t h e l i v e r due t o t h e s i m i l a r c o n c e n t r a t i o n s o f r a d i o p h a r m a c e u t i c a l w i t h i n e a c h o r g a n . c ) N a I - 1 3 1 (6% HSA) N a I - 1 3 1 i n a 6% s o l u t i o n o f human s e r u m a l b u m i n was i n v e s t i g a t e d t o o b s e r v e i t s b i o l o g i c a l b e h a v i o r i n c o m p a r i s o n t o t h e r a d i o i o d i n a t e d f a t t y a c i d s . The N a I - 1 3 1 was d i s s o l v e d i n t h e 6% HSA t o p r o v i d e t h e same v e h i c l e f o r i n j e c t i o n a s t h e r a d i o i o d i n a t e d f a t t y a c i d s . S i n c e i t was b e l i e v e d t h a t I o d i d e - 1 3 1 was r e l e a s e d by h y d r o l y s i s o f t h e m e t a b o l i c p r o d u c t o f B e t a o x i d a t i o n , t h e d i s t r i b u t i o n s t u d i e s s h o u l d be s i m i l a r i n t h e l a t t e r s t a g e s o f t h e s t u d y . The r e s u l t s o f t h e " p e r c e n t i n j e c t e d d o s e p e r t o t a l o r g a n " a r e shown i n T a b l e 13 a n d F i g u r e 1 3 . The b l o o d l e v e l o f N a I - 1 3 1 was e x t r e m e l y h i g h a n d showed a s t e a d y d e c r e a s e w i t h t i m e . T h i s b l o o d l e v e l was h i g h e r t h a n t h a t o b s e r v e d f o r t h e two r a d i o i o d i n a t e d f a t t y a c i d s . The m y o c a r d i a l c o n c e n t r a t i o n was l o w e r t h a n t h e c o n c e n t r a t i o n i n t h e l i v e r , t h e k i d n e y , a s w e l l a s t h e l u n g s . I n t h e 6 h o u r s t u d y , t h e m y o c a r d i a l l e v e l o f N a I - 1 3 1 a p p e a r e d t o be c o n s t a n t . T h i s was a l s o t r u e f o r t h e r a d i o a c t i v i t y i n t h e l u n g s , w h i c h was a l m o s t i n d i s t i n g u i s h a b l e f r o m t h a t o f t h e h e a r t . The k i d n e y c o n c e n t r a t i o n o f t h e N a I - 1 3 1 d i d n o t f l u c t u a t e n o t i c e a b l y b u t d e c r e a s e d g r a d u a l l y w i t h t i m e . The h e p a t i c c o n c e n t r a t i o n p e a k e d a t . 0 3 3 h o u r s , a f t e r w h i c h t h e r e was a g r a d u a l T A B L E X I I I T o t a l U p t a k e o f N a I - 1 3 1 ( 6 % H S A ) b y t h e S p l e e n , S t o m a c h I n t e s t i n e s , M u s c l e , a n d B o n e o f M i c e a , b m e ( h o u r s ) S p l e e n S t o m a c h I n t e s t i n e s M u s c l ec B o n e d . 0 1 6 . 3 7 1 . 0 4 . 8 2 ± . 0 7 2 . 7 9 1 . 2 1 1 7 . 9 2 t . 8 2 4 . 2 8 t . 1 6 . 0 3 3 . 3 3 ± . 0 3 . 9 7 ± . 0 8 3 . 5 2 1 . 7 7 1 5 . 8 4 i . 9 7 3 . 6 9 t . 0 9 . 0 5 0 . 3 2 1 . 0 3 1 . 1 6 1 . 0 8 2 . 2 6 1 . 1 6 1 5 . 5 5 i . 4 1 4 . 0 6 t . , 2 2 . 0 8 3 . 3 2 1 . 0 2 1 . 5 1 1 : 1 7 1 . 8 2 1 . 0 7 1 4 . 0 5 1 . 5 0 3 . 5 5 t . . 1 0 . 1 6 7 . 2 2 ± . 0 1 2 . 1 2 + . 4 3 1 . 7 3 1 . 1 1 1 2 . 7 2 t . 3 8 3 . 4 3 i . . 3 2 . 5 0 0 . 2 1 1 . 0 1 1 . 8 H . 2 7 1 . 4 4 1 . 1 1 7 . 9 5 1 . 3 7 1 . 8 8 t . . 0 3 1 . 0 0 0 . 1 8 1 . 0 3 1 . 7 7 1 . 1 9 1 . 1 9 1 . 0 7 6 . 5 1 t . 3 1 1 . 5 8 t . . 0 5 4 . 0 0 0 . 0 9 1 . 0 1 1 . 3 4 1 . 2 5 . 6 8 1 . 0 4 3 . 4 0 1 . 5 6 . 8 1 t . 0 9 6 . 0 0 0 . 0 6 1 . 0 1 1 . 1 2 1 . 3 1 . 5 9 t . l l 2 . 8 2 1 . 3 7 . . 7 2 i . 1 3 a 1 3 1 E x p r e s s e d a s p e r c e n t o f I - H S A p e r t o t a l o r g a n b M e a n v a l u e s f r o m f i v e m i c e i s t a n d a r d d e v i a t i o n o f t h e m e a n c T o t a l m u s c l e w a s c a l c u l a t e d o n 4 5 p e r c e n t o f b o d y w e i g h t ( S t a n d e t a l , 1 9 6 2 ) T o t a l b o n e w a s c a l c u l a t e d a s 6 p e r c e n t o f b o d y w e i g h t ( S t a n d e t a l . , 1 9 6 2 ) T o t a l O r g a n U p t a k e o f N a I - 1 3 1 ( H S A ) by L i v e r , H e a r t , L u n g , K i d n e y s , and B l o o d i n M i c e 3 a R a d i o a c t i v i t y l e v e l s h a v e been d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . 114 d e c r e a s e i n c o n c e n t r a t i o n o f N a I - 1 3 1 . The s t o m a c h c o n c e n t r a t i o n o f N a I - 1 3 1 p e a k e d a t . 1 6 7 h o u r s , a n d t h e n d e c r e a s e d s l o w l y . T h i s p e a k p r o b a b l y r e p r e s e n t e d e x c r e t i o n o f I o d i d e - 1 3 1 i n t o t h e g a s t i c j u i c e s ( M y a h t e t a l . , 1 9 5 0 ) . T h e m u s c l e , t h e b o n e , t h e i n t e s t i n e s , a n d t h e s p l e e n showed no a f f i n i t y f o r t h e r a d i o i o d i d e , a n d t h e d e c r e a s e i n t h e o r g a n s was r a p i d , s h o w i n g l e s s t h a n 1% o f t h e i n j e c t e d d o s e a t 6 h o u r s , w i t h t h e e x c e p t i o n o f t h e m u s c l e . T a b l e 14 a n d F i g u r e 14 r e p r e s e n t e d t h e " p e r c e n t i n j e c t e d d o s e p e r g r a m o r g a n " o r t h e " p e r c e n t i n j e c t e d d o s e p e r ml b l o o d " . The b l o o d c o n c e n t r a t i o n was h i g h e r t h a n t h a t o f t h e o t h e r o r g a n s . The k i d n e y a c c u m u l a t e d a p e a k c o n c e n t r a t i o n o f 6 . 5 % p e r g r a m o r g a n a t . 0 3 3 a n d . 0 5 0 h o u r s . T h i s was p r o b a b l y due t o t h e b l o o d f l o w t o t h e k i d n e y s . I n t h e k i d n e y , t h e i o d i d e i s f i l t e r e d by t h e g l o m e r u l i a n d a b o u t 73% i s r e a b s o r -b e d by t h e t u b u l e s ( M y a n t e t a l . , 1 9 5 0 ; P e r l man e t a l . , 1 9 4 1 ) . The k i d n e y c o n c e n t r a t i o n was f o l l o w e d by t h e c o n c e n t r a t i o n o f N a I - 1 3 1 by t h e l u n g s , t h e h e a r t , a n d t h e n t h e l i v e r . The r e l a t i v e o r g a n u p t a k e was s i m i l a r f o r t h e bone and t h e s p l e e n , i n w h i c h r a d i o a c t i v i t y a l s o d e c r e a s e d i n a s i m i l a r m a n n e r . F o r t h e s p l e e n , t h e i n t e s t i n e s , as w e l l a s t h e b o n e , t h e c a l c u l a t e d p e r c e n t i n j e c t e d d o s e p e r g r a m was l e s s t h a n . 6 1 % by 6 h o u r s . The e x c e p t i o n was t h e c o n c e n t r a t i o n o f t h e N a I - 1 3 1 by t h e s t o m a c h . A l t h o u g h t h e p e a k l e v e l was o b s e r v e d a t . 5 h o u r s , t h e c o n c e n t r a t i o n was s t i l l 5 . 7 9 % a t 6 h o u r s a f t e r i n j e c t i o n . The d i s t r i b u t i o n s t u d i e s s h o w i n g " p e r c e n t i n j e c t e d d o s e p e r gram o r g a n / p e r c e n t i n j e c t e d d o s e p e r ml b l o o d " a r e d e p i c t e d i n T a b l e 15 a n d F i g u r e 1 5 . The k i d n e y s s h o w e d t h e h i g h e s t o r g a n / b l o o d T A B L E X I V R e l a t i v e O r g a n U p t a k e o f N a I - 1 3 1 ( 6 % H S A ) i n M i c e a , b i m e ( h o u r s ) S p l e e n S t o m a c h I n t e s t i n e s M u s c l e B o n e . 0 1 6 2 . 4 7 + . 1 4 3 . 8 7 ± . 4 0 1 . 8 5 + . 0 7 1 . 3 4 + . 0 9 2 . 7 4 ± . 1 2 . 0 3 3 2 . 0 9 + . 0 6 4 . 4 0 ± . 4 7 3 . 0 7 ± . 7 0 1 . 3 8 + . 0 6 2 . 4 3 ± . 1 0 . 0 5 0 2 . 4 3 ± . l 5 5 . 7 3 ± . 2 0 1 . 7 8 + . 0 5 1 . 3 5 + . 0 2 2 . 6 1 + . 1 4 . 0 8 3 2 . 1 7 ± . 0 8 6 . 3 7 + , . 4 6 1 . 4 8 ± . 0 4 1 . 1 8 ± . 0 4 2 . 2 4 + . 0 3 . 1 6 7 2 . 0 7 ± . l l 9 . 9 4 + 1 . . 3 9 1 . 6 1 ± . 0 4 1 . 1 4 + . 0 2 2 . 3 3 + . 2 6 . 5 0 0 1 . 5 6 ± . 1 1 8 . 7 2 i l . . 0 1 1 . 1 1 ± . 0 7 . 6 9 ± . 0 4 1 . 2 1 1 . 0 4 1 . 0 0 0 1 . 2 4 ± . 0 3 8 . 8 7 + 1 , . 1 9 . 9 9 + . 0 5 . 5 7 ± . 0 3 1 . 0 4 + . 0 4 4 . 0 0 0 . 6 0 1 . 0 7 5 . 6 9 + , . 9 2 . 4 9 ± . 0 3 . 2 9 ± . 0 5 . 5 3 1 . 0 6 6 . 0 0 0 . 6 1 1 . 0 9 5 . 7 9 + 1 , . 3 8 . 5 8 ± . 0 7 . 2 7 1 . 0 7 . 5 3 1 . 0 8 E x p r e s s e d as percent of i n j e c t e d 1 3 1 I - H S A per gm of organ weight. b M e a n value from f i v e mice t standard e r r o r o f the mean. F i g u r e 14 R e l a t i v e U p t a k e o f N a I - 1 3 1 (HSA) by L i v e r H e a r t , L u n g , K i d n e y s , and B l o o d i n M i c e 3 a R a d i o a c t i v i t y l e v e l s have been d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . T A B L E X V O r g a n / B l o o d D i s t r i b u t i o n o f N a I - 1 3 1 [6Z H S A ) i n M i c e a ' T i m e ( h o u r s ) S p l e e n S t o m a c h I n t e s t i n e s M u s c l e B o n e  B l o o d B l o o d B l o o d B l o o d B l o o d . 0 1 6 . 2 3 ± . 0 2 . 3 6 1 . 0 3 . 1 8 1 . 0 0 . 1 3 ± . 0 1 . 2 6 i . 0 1 . 0 3 3 . 2 5 1 . 0 1 . 5 3 1 . 0 5 . 3 7 1 . 0 9 . 1 7 ± . 0 1 . 3 0 + . 0 1 . 0 5 0 . 2 9 1 . 0 2 . 6 8 + . 0 3 . 2 1 ± . 0 1 . 1 6 + . 0 1 . 3 1 + . 0 2 . 0 8 3 . 3 3 1 . 0 2 . 9 7 1 . 0 8 .22+. 00 . 1 8 1 . 0 1 .34+.00 . 1 6 7 . 3 6 1 . 0 1 1 . 7 3 1 . 2 4 . 2 8 1 . 0 1 . 2 0 + . 0 0 . 4 0 + . 0 4 . 5 0 0 . 4 2 1 . 0 2 2 . 3 5 1 . 2 7 . 2 9 1 . 0 1 . 1 9 i . 0 1 . 3 3 ± . 0 0 1 . 0 0 0 . 4 1 1 . 0 1 2 . 9 2 1 . 3 7 . 3 3 + . 0 1 . 1 9 ± . 0 1 . 3 4 i . 0 1 4.000 . 3 9 1 . 0 2 3 . 6 4 1 . 3 7 . 3 3 1 . 0 3 . 1 9 + . 0 2 . 3 4 i . 0 1 6.000 . 3 8 1 . 0 3 3.441.53 . 3 5 1 . 0 2 . 1 7 1 . 0 1 . 3 2 1 . 0 3 E x p r e s s e d a s a r a t i o o f p e r c e n t i n j e c t e d d o s e p e r g m o f o r g a n t o p e r c e n t i n j e c t e d d o e s p e r m l o f b l o o d . M e a n v a l u e s f r o m f i v e m i c e i s t a n d a r d e r r o r o f t h e m e a n . o l i v e r 01 .1 1.0 10 T i m * ( h o u r s ) F i g u r e 15 O r g a n / B l o o d D i s t r i b u t i o n o f N a I - 1 3 1 ( H S A ) by L i v e r , H e a r t , L u n g , and K i d n e y s i n M i c e 3 3 R a d i o a c t i v i t y l e v e l s have been d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . 119 r a t i o , w h i c h was f o l l o w e d by t h e l u n g s , t h e h e a r t , a n d t h e n t h e l i v e r . T h i s c o u l d be e x p e c t e d a s t h e k i d n e y s a r e h i g h l y v a s c u l a r a n d w o u l d f i l t e r t h e I o d i d e - 1 3 1 p r e s e n t e d by t h e b l o o d . The o r g a n / b l o o d r a t i o s f o r t h e s p l e e n , t h e i n t e s t i n e s , t h e m u s c l e , and t h e bone w e r e r e l a t i v e l y c o n s t a n t i n t h e 6 h o u r s t u d y . The s t o m a c h / b l o o d r a t i o p e a k e d a t 4 h o u r s , a n d t h e n d e c r e a s e d . 131 131 d) C o m p a r a t i v e M y o c a r d i a l U p t a k e o f I - C a p r i c A c i d , I - L a u r i c A c i d , a n d N a I - 1 3 1 (6% HSA) I t i s a p p a r e n t f r o m F i g u r e 16 t h a t t h e r a d i o i o d i n a t e d f a t t y a c i d s w e r e c o n c e n t r a t e d by t h e h e a r t i n s i g n i f i c a n t l y h i g h e r q u a n t i t i e s t h a n t h e N a I - 1 3 1 (6% H S A ) . The h i g h e r u p t a k e o f t h e r a d i o i o d i n a t e d f a t t y a c i d s by t h e h e a r t was e v i d e n t up t o .1 h o u r s p o s t - i n j e c t i o n , a f t e r w h i c h t h e r a t e o f d e c l i n e o f a l l t h r e e compounds c l o s e l y r e s e m b l e d o n e a n o t h e r . T h i s was t o be e x p e c t e d s i n c e o n e o f t h e m e t a b o l i c e n d p r o d u c t s o f t h e B e t a o x i d a t i o n o f i o d o f a t t y a c i d s was i o d o a c e t a t e , w h i c h was l i b e r a t e d i n t o t h e b l o o d s t r e a m ( R o b i n s o n a n d L e e , 1 9 7 5 ) . H o w e v e r , t h e i o d o a c e t a t e i s r e a c t i v e a n d u n s t a b l e due m a i n l y t o t h e w e a k n e s s o f t h e c a r b o n - i o d i n e bond. ( W e b b , 1 9 6 6 ) . D e c o m p o s i t i o n o c c u r s r e l e a s i n g i o d i d e i o n s a n d i o d i n e . T h i s r e l e a s e d I o d i d e - 1 3 1 b e h a v e d i n an i d e n t i c a l m a n n e r t o t h e N a I - 1 3 1 (6% H S A ) , t h u s c o n f i r m i n g t h a t i t was t h e e x i s t a n c e o f t h e i o d i d e i o n w h i c h a c c o u n t e d f o r t h e b i o l o g i c a l d i s t r i b u t i o n o f t h e i o d o f a t t y a c i d s a f t e r t h e f i r s t .1 h o u r . I n F i g u r e 1 7 , a c o m p a r a b l e d e c l i n e i n r a d i o p h a r m a c e u t i c a l o T i m * (hours) F i g u r e 16 T o t a l M y o c a r d i a l U p t a k e o f 1 0 - I o d o d e c a n o i c A c i d 1 2 - I o d o l a u r i c A c i d , a n d N a l - l 3 1 ( H S A ) i n M i c e a a R a d i o a c t i v i t y l e v e l s h a v e been d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . F i g u r e 17 R e l a t i v e M y o c a r d i a l U p t a k e o f 1 0 - I o d o d e c a n o i c A c i d , 1 2 - I o d o l a u r i c A c i d , a n d N a I - 1 3 1 ( H S A ) i n M i c e 9 a R a d i o a c t i v i t y l e v e l s h a v e b e e n d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . 122 c o n c e n t r a t i o n p e r g r a m o f m y o c a r d i u m c o u l d be s e e n . The h i g h e r m y o c a r d i a l u p t a k e o f r a d i o i o d i n a t e d f a t t y a c i d s was a g a i n e v i d e n t i n c o m p a r i s o n t o N a I - 1 3 1 , t h u s i n d i c a t i n g t h e p r e f e r e n t i a l u p t a k e o f f a t t y a c i d s by t h e h e a r t . I t a p p e a r e d t h a t 1 2 - i o d o l a u r i c a c i d had a h i g h e r i n i t i a l m y o c a r d i a l c o n c e n t r a t i o n t h a n t h e 1 0 - i o d o c a p r i c a c i d a l t h o u g h t h i s d i f f e r e n c e was no l o n g e r e v i d e n t a t . 0 5 h o u r s . F i g u r e 18 g r a p h i c a l l y i n d i c a t e d t h e d i f f e r e n c e s o f t h e 131 131 m y o c a r d i a l / b l o o d r a t i o s f o r t h e I - c a p r i c a c i d , t h e I - l a u r i c a c i d , a n d t h e N a I - 1 3 1 (6% H S A ) . The f i g u r e c l e a r l y d e p i c t e d t h e s u p e r i o r m y o c a r d i a l / b l o o d r a t i o s o f t h e r a d i o i o d i n a t e d f a t t y a c i d s . 131 131 The r a t i o s f o r t h e I - c a p r i c a c i d a n d I - l a u r i c a c i d w e r e s i m i l a r , s h o w i n g d e c r e a s i n g r a t i o s u n t i l 1 h o u r a f t e r i n j e c t i o n . From 1 h o u r , t h e m y o c a r d i u m / b l o o d r a t i o s i n c r e a s e d a s t h e b l o o d was c l e a r e d o f r a d i o a c t i v i t y . F o r a m y o c a r d i a l s c a n n i n g a g e n t , t h e l o c a l i z a t i o n o f t h e r a d i o n u c l i d e a s w e l l a s t h e t a r g e t / n o n - t a r g e t r a t i o s a r e e q u a l l y i m p o r t a n t . From t h e d i s t r i b u t i o n s t u d i e s , i t was e v i d e n t t h a t b o t h r a d i o i o d i n a t e d f a t t y a c i d s a p p e a r e d t o be e x t r a c t e d by t h e h e a r t t o a g r e a t e r e x t e n t t h a n t h e N a I - 1 3 1 ( 6 % H S A ) . W h i l e t h e m y o c a r d i a l c o n c e n t r a t i o n o f 1 2 - i o d o l a u r i c a c i d a p p e a r e d h i g h e r t h a n t h e 1 0 - i o d o -c a p r i c a c i d , t h e m y o c a r d i u m / b l o o d r a t i o s w e r e s i m i l a r . I n a d d i t i o n , t h e s i m i l a r c o n c e n t r a t i o n o f 1 2 - i o d o l a u r i c a c i d by t h e l i v e r and t h e l u n g c o m p a r e d t o t h e h e a r t c o u l d p r e s e n t p o t e n t i a l p r o b l e m s i n m y o c a r d i a l s c a n n i n g . The d i f f e r e n c e s n o t e d i n t h e d i s t r i b u t i o n s t u d i e s d i d n o t ro u> T i m * ( h o u r t j F i g u r e 18 M y o c a r d i a l / B l o o d D i s t r i b u t i o n o f 1 0 - I o d o d e c a n o i c A c i d , 1 2 - I o d o l a u r i c A c i d , and N a I - 1 3 1(HSA) i n M i c e 9 a R a d i o a c t i v i t y l e v e l s h a v e b e e n d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . 124 a p p e a r c o n c l u s i v e a s t o w h i c h i o d o f a t t y a c i d w o u l d be s u p e r i o r f o r m y o c a r d i a l s c a n n i n g . T h e r e f o r e i t was d e c i d e d t o p r o c e e d w i t h f u r t h e r s t u d i e s u s i n g b o t h r a d i o i o d i n a t e d f a t t y a c i d s . I n t h e s e d i s t r i b u t i o n s t u d i e s t h e m o l a r r a t i o s o f f a t t y a c i d / a l b u m i n w e r e a p p r o x i m a t e l y 3 . T h i s was c a l c u l a t e d on t h e b a s i s o f t h e t o t a l b r o m o f a t t y a c i d u s e d i n t h e f i n a l v o l u m e o f 6% human s e r u m a l b u m i n . The m o l a r r a t i o s u s e d w e r e w i t h i n p h y s i o l o g i c l i m i t s and s h o u l d n o t h a v e i n t e r f e r e d w i t h m y o c a r d i a l e x t r a c t i o n . 5 . T o x i c i t y S t u d i e s a ) 1 2 - B r o m o l a u r i c A c i d The s o d i u m b r o m o l a u r a t e s o l u t i o n u s e d had a f i n a l c o n c e n t r a t i o n o f lOmg/ml a n d a m o l a r r a t i o o f 2 4 . 3 5 : 1 o f f a t t y a c i d t o a l b u m i n . A t l e a s t 7 g r o u p s o f m i c e w e r e u s e d t o s t u d y t h e t o x i c i t y o f 1 2 - b r o m o l a u r i c a c i d . E a c h g r o u p c o n s i s t e d o f a minimum o f 6 m i c e . The c o n t r o l g r o u p s a l s o c o n s i s t e d o f 6 m i c e . The m i c e w e r e o b s e r v e d i m m e d i a t e l y a f t e r i n j e c t i o n a n d f o r a p e r i o d o f 7 s u c c e e d i n g d a y s t o o b s e r v e a n y t o x i c e f f e c t s w h i c h may n o t m a n i f e s t i t s e l f i m m e d i a t e l y . H o w e v e r , i t a p p e a r e d t h a t i f t h e mouse s u r v i v e d f o r t h e f i r s t 5 m i n u t e s a f t e r t h e i n j e c t i o n , i t w o u l d n o t d i e a n d w o u l d a p p e a r t o be n o r m a l . F o r s o d i u m b r o m o l a u r a t e , t h e i n j e c t i o n v o l u m e s v a r i e d f r o m . 2 5 ml . t o . 5 0 m l . S i n c e t h e i n j e c t i o n v o l u m e s w e r e i n c o n s i s t e n t , s a m p l e s o f 10% human s e r u m a l b u m i n e q u i v a l e n t t o t h e l a r g e s t v o l u m e a d m i n i s t e r e d was i n j e c t e d i n t o a c o n t r o l g r o u p . T h i s was t o a s c e r t a i n t h a t a n y t o x i c e f f e c t s o b s e r v e d w e r e n o t due t o t h e v o l u m e i n j e c t e d . 125 The v o l u m e a c c e p t a b l e f o r r a p i d i n t r a v e n o u s i n j e c t i o n v a r i e s f r o m . 1 0 ml - . 5 0 ml f o r r o d e n t s ( B a l a z , 1 9 7 0 ) . T h e r e f o r e , t h e maximum d o s e i n j e c t e d was w i t h i n t h e a c c e p t a b l e v o l u m e r a n g e . The c o n t r o l g r o u p o f m i c e d e m o n s t r a t e d no a d v e r s e e f f e c t s when i n j e c t e d w i t h i t h e . maximum v o l u m e o f . 5 0 m l . The i n j e c t i o n was made o v e r a p e r i o d o f 10 s e c o n d s . The r e s u l t s o f t h e t o x i c i t y s t u d y f o r s o d i u m b r o m o -l a u r a t e a r e g i v e n i n T a b l e 16', a c c o r d i n g t o t h e m e t h o d o f L i t c h f i e l d a n d W i l c o x i n ( 1 9 4 9 ) . 2 The v a l u e o f ( c h i ) f o r 4 d e g r e e s o f f r e e d o m was 9 . 4 9 . S i n c e 2 . 7 2 i s l e s s t h a n 9 . 4 9 , t h e d a t a was n o t s i g n i f i c a n t l y h e t e r o g e n e o u s . The LD-|6 was 183 m g / K g ; t h e L D 5 Q was 210 m g / K g ; w h i l e t h e LDg^ was 236 m g / K g . The s l o p e f u n c t i o n ( s ) was c o m p u t e d a s : S = L D 8 4 / L D 5 Q + L D 5 0 / L D ] 6 = 2 3 6 / 2 1 0 + 2 1 0 / 1 8 3 = 1 . 1 4 The t o t a l number o f a n i m a l s t e s t e d b e t w e e n t h e e x p e c t e d e f f e c t s o f 16% - 84% was d e s i g n a t e d N 1 a n d c o n s i s t e d o f 2 0 m i c e . The f ( L D g g ) was c a l c u l a t e d by t h e f o r m u l a : SZ.77M- = s e x P ° n e n t = 1 . 1 4 ( ' 6 1 9 4 ) = 1 . 0 8 4 6 The u p p e r l i m i t s and l o w e r l i m i t s f o r t h e 95% c o n f i d e n c e l e v e l w e r e c a l c u l a t e d b y ( L D 5 0 ) x f ( L D 5 Q ) a n d : ( . L D 5 0 ) / f ( L D 5 Q ) r e s p e c t i v e l y . The u p p e r l i m i t was f o u n d / t o be 228 mg/Kg w h i l e t h e l o w e r l i m i t was f o u n d t o be 194 m g / K g . T h e r e f o r e , t h e i n t r a v e n o u s L D ^ Q o f s o d i u m b r o m o -l a u r a t e was 21.0 mg/Kg (194mg/Kg - 2 2 8 m g / K g ) . Dose nig/Kg 1 3 9 167 175 2 0 0 2 2 5 2 5 0 TABLE XVI D e t e r m i n a t i o n o f t h e I n t r a v e n o u s L D 5 Q f o r N a - B r o m o l . a u r a t e i n 16% Human S e r u m A l b u m i n S o l u t i o n i n M i c e . N o . d e a d N o . t e s t e d 0 / 6 0 / 6 1/6 5 / 1 0 6 / 1 0 6 / 6 ' O b s e r v e d % Dead 0 ( . 1 5 ) 0 ( 1 . 1 ) 1 6 . 7 50 6 0 100 ( 9 7 . 7 ) E x p e c t e d % Dead . 0 5 3 . 3 7 . 5 3 7 . 0 7 2 . 0 9 3 . 0 N o . - No. O b s e r v e d E x p e c t e d . 1 0 2 . 2 9 . 2 1 3 . 0 1 2 . 0 4 . 7 C o n t r i b u t i o n t o ( C h i ) 2 . 0 0 2 . 0 1 5 . 1 2 0 . 1 0 5 . 0 9 5 . 0 3 4 Z = . 3 7 1 T o t a l N o . o f A n i m a l s = 44 D e g r e e s o f f r e e d o m N=K-2=4 N o . o f d o s e s K=6 A n i m a l s / d o s e = 7 . 3 3 ( C h i ) 2 = 7 . 3 3 x .371 = 2 . 7 2 1 2 7 The s o d i u m s a l t o f b r o m o l a u r i c a c i d c a n be c o n s i d e r e d a r e l a t i v e l y t o x i c s u b s t a n c e s i n c e t h e L D ^ Q was f o u n d t o be 2 1 0 mg/Kg as c o m p a r e d t o 7 5 0 mg/Kg f o r n o n - t o x i c compounds ( C h r i s t i a n s o n , 1 9 7 3 ) . The p u b l i s h e d L D ^ Q f o r i n t r a v e n o u s l y a d m i n i s t e r e d l a u r i c a c i d i s 1 3 1 mg/Kg (O ro and W r e t l i n d , 1 9 6 1 ) . T h e r e i s no L D 5 Q v a l u e l i s t e d f o r b r o m o l a u r i c a c i d . I t m u s t be r e m e m b e r e d t h a t t h e r e s u l t s o b t a i n e d by Oro a n d W r e t l i n d ( 1 9 6 1 ) w e r e f o r . a 2 % e m u l s i o n o f l a u r i c a c i d i n c o t t o n s e e d o i l . T h i s l o w e r t o x i c i t y o b s e r v e d i n o u r e x p e r i m e n t a l r e s u l t s c o u l d p r o b a b l y be a t t r i b u t e d i n p a r t t o t h e v e h i c l e u s e d . W h i l e a l b u m i n - s o l u t i o n c a n be c o n s i d e r e d p h y s i o l o g i c a l , c o t t o n s e e d o i l c a n n o t be c o n s i d e r e d p h y s i o l o g i c a l , a l t h o u g h c o t t o n s e e d o i l h a s shown l i t t l e o r no t o x i c e f f e c t s d u r i n g i n t r a v e n o u s i n j e c t i o n s i n t o m i c e ( O r o a n d W r e t l i n d , 1 9 6 1 ) . F o r s o d i u m b r o m o l a u r a t e , t h e f i r s t i n d i c a t i o n s o f t o x i c i t y i n c l u d e d s l a c k e n i n g o f t h e l i m b s and l o s s o f t h e r i g h t i n g r e f l e x , a c c o m p a n i e d by p r o f u s e d e f e c a t i o n . A t t h e h i g h e r i n j e c t i o n d o s e s , t h e m i c e s u f f e r e d f r o m p a l p i t a t i o n s , s e d a t i o n , t w i t c h i n g , t r e m o r s , f o l l o w e d by t o n i c c o n v u l s i o n s w h i c h r e s u l t e d i n d e a t h . The t o x i c e f f e c t s o b s e r v e d f o r 2 % l a u r i c a c i d w e r e c o m p a r a b l e t o t h o s e o b s e r v e d f o r s o d i u m b r o m o l a u r a t e . I n b o t h c a s e s , d e a t h a p p e a r e d t o be c a u s e d by r e s p i r a t o r y f a i l u r e ( B a l a z , 1 9 7 0 ; Oro a n d W r e t l i n d , 1 9 6 1 ) . The d y s p n e a a n d c o n v u l s i o n s w e r e p r o b a b l y s e c o n d a r y t o a n o x i a (Oro a n d W r e t l i n d , 1 9 6 1 ) . M a s s i v e p u l m o n a r y edema h a s b e e n s u g g e s t e d as t h e c a u s e o f d e a t h a f t e r a d m i n i s t r a t i o n o f o l e i c a c i d t o d o g s ( J e f f e r s o n a n d N e c h e l e s , 1 9 4 8 ) . A t t e m p t s w e r e made i n o u r e x p e r i m e n t s t o e x a m i n e t h e l u n g s i m m e d i a t e l y f o l l o w i n g d e a t h o f t h e 128 m i c e . A l t h o u g h t h e l u n g s w e r e s o m e t i m e s s p e c k l e d w i t h b l o o d , t h e t h o r a c i c c a v i t y was n o t e d e m a t o u s . H o w e v e r , o n l y g r o s s m a c r o s c o p i c a p p e a r a n c e was n o t e d a n d no f u r t h e r m i c r o s c o p i c e x a m i n a t i o n s w e r e p e r f o r m e d , t h u s t h e p r e c i s e c a u s e o f d e a t h was d i f f i c u l t t o i n t e r p r e t . B r o m o a c e t a t e , a m e t a b o l i t e o f t e r m i n a l l a b e l e d b r o m o f a t t y a c i d m e t a b o l i s m , may a l s o c o n t r i b u t e t o t h e t o x i c e f f e c t s o b s e r v e d a f t e r t h e a d m i n i s t r a t i o n o f t h e b r o m o f a t t y a c i d s . The a d m i n i s t r a t i o n o f t h e r a d i o i o d i n a t e d f a t t y a c i d i s a l w a y s a c c o m p a n i e d by t h e s i m u l t a n e o u s a d m i n i s t r a t i o n o f t h e p a r e n t c o m p o u n d , t h e b r o m o f a t t y a c i d . I o d o a c e t a t e , t h e m e t a b o l i t e o f i o d o f a t t y a c i d m e t a b o l i s m , i s a l s o a t o x i c c o m p o u n d . H o w e v e r , o n l y t r a c e q u a n t i t i e s a r e a d m i n i s t e r e d s o i t n e e d n o t be o f g r e a t c o n c e r n . A l m o s t 10 mg o f t h e b r o m o f a t t y a c i d c o u l d be a d m i n i s t e r e d a l o n g w i t h t h e r a d i o i o d i n a t e d f a t t y a c i d . From 10 mg o f b r o m o l a u r i c o r b r o m o c a p r i c a c i d , 4 . 3 mg o f b r o m o a c e t a t e may be p r o d u c e d by c o m p l e t e m e t a b o l i s m by B e t a o x i d a t i o n ( R o b i n s o n , 1 9 7 7 ) . . T h e b r o m o a c e t a t e i s s u b j e c t t o h y d r o l y s i s , a s i s a p p a r e n t w i t h t h e i o d o a c e t a t e , w i t h t h e m a j o r p a r t o f t h e compound b e i n g h y d r o l y s e d t o t h e h a l i d e i o n w i t h i n 10 m i n u t e s i n t h e b l o o d ( P o e e t a l . , 1 9 7 6 b ) . The L D ^ Q o f b r o m o a c e t a t e h a s b e e n r e p o r t e d t o be lOOmg/Kg i n w h i t e m i c e f o r c e d f e d an a q u e o u s s o l u t i o n ( M o r r i s o n , 1 9 4 6 ) . I t h a s b e e n f o u n d t o c a u s e p r o g r e s s i v e r e s p i r a t o r y a n d c a r d i a c d e p r e s s i o n (Webb, 1 9 6 6 ) . T r e m o r s , t o n i c c o n v u l s i o n s , , and c h a n g e s i n t h e m u s c u l a r s y s t e m c a u s e w e a k n e s s and p a r a l y s i s , f o l l o w e d by d e a t h o f t h e a n i m a l . I n t r a v e n o u s i n j e c t i o n s o f 50 mg/Kg o f b r o m o a c e t a t e h a s b e e n o b s e r v e d t o c a u s e g e n e r a l m u s c l e r i g o r , f o l l o w e d by d e a t h ( W e b b ; , . 1 9 6 6 ) . 129 I t i s a p p a r e n t t h a t c a r e m u s t be t a k e n t o e n s u r e t h a t t h e m i n i m a l amount o f u n l a b e l e d b r o m o f a t t y a c i d i s a d m i n i s t e r e d . H o w e v e r , e v e n w i t h t h e a d m i n i s t r a t i o n o f 10 mg o f t e r m i n a l b r o m i n a t e d f a t t y a c i d , t h e amount o f b r o m o a c e t a t e p r o d u c e d i s w e l l b e l o w t h e t o x i c d o s e . R o b i n s o n ( 1 9 7 7 ) h a s s i n c e d e v i s e d a m e t h o d w h e r e b y s m a l l e r i n i t i a l q u a n t i t i e s o f omega b r o m o c a r b o x y l i c a c i d s c o u l d be u s e d , t h u s e l i m i n a t i n g t h e a d m i n i s t r a t i o n o f u n n e c e s s a r y u n l a b e l e d b r o m i n a t e d f a t t y a c i d s . b) 1 0 - B r o m o c a p r i c A c i d The v e h i c l e f o r t h e b r o m o c a p r i c a c i d was d i s t i n c t l y d i f f e r e n t f r o m 10% H S A , a s p r e v i o u s l y d e s c r i b e d . The r e s u l t s o b t a i n e d f r o m t h e s e t o x i c i t y s t u d i e s w o u l d n o t n e c e s s a r i l y r e f l e c t t h e t o x i c e f f e c t s o f t h e b r o m o c a p r i c a c i d a l o n e . The t o x i c i t y o f t h e o t h e r c o m p o n e n t s o f t h e v e h i c l e m u s t a l s o be t a k e n i n t o c o n s i d e r a t i o n . A t o t a l o f 7 g r o u p s o f m i c e w e r e u s e d f o r t h e i n c r e m e n t d o s e s f o r t h e t o x i c i t y s t u d y i n a d d i t i o n t o t h e c o n t r o l g r o u p s . E a c h g r o u p c o n s i s t e d o f a minimum o f s i x m i c e . The v o l u m e s i n j e c t e d v a r i e d f r o m . 1 2 ml t o . 1 8 m l . C o n t r o l g r o u p s w e r e i n j e c t e d w i t h v a r y i n g q u a n t i t i e s o f v e h i c l e w i t h o u t t h e b r o m o c a p r i c a c i d up t o a v o l u m e o f . 2 0 m l . T h e o n l y e f f e c t o b s e r v e d was t h a t t h e m i c e a p p e a r e d i n a c t i v e a n d s l u g g i s h . H o w e v e r , t h e s e e f f e c t s a p p e a r e d t o be t r a n s i e n t , w i t h t h e m i c e r e c o v e r i n g t o f u l l a c t i v i t y w i t h i n a few m i n u t e s . The v a l u e o f ( c h i ) f o r 5 d e g r e e s o f f r e e d o m was c a l c u l a t e d t o be 1 1 . 1 ( L i t c h f i e l d and W i l c o x i n , 1 9 4 9 ) . The e x p e r i m e n t a l ( c h i ) TABLE X V I I D e t e r m i n a t i o n o f t h e I n t r a v e n o u s L D 5 Q f o r 1 0 - B r o m o c a p r i c A c i d S o l u t i o n i n M i c e Dose mg/Kg No. d e a d O b s e r v e d % E x p e c t e d % No. - No. C o n t r i b u t i o n No. t e s t e d Dead Dead O b s e r v e d E x p e c t e d t o ( C h i ) 2 71 0 / 6 0 ( . 0 3 ) .1 . 0 7 . 0 0 1 77 1 / 1 0 10 5 5 . 0 . 0 5 0 8 4 2 / 6 3 3 . 3 33 . 3 0 — 8 6 4 / 1 0 4 0 . 0 40 0 — 87 8 / 1 0 8 0 . 0 56 24 . 2 3 5 9 8 9 / 1 0 9 0 . 0 9 7 . 5 7 . 5 . 2 3 0 99 6 / 6 1 0 0 . 0 ( 9 9 . 7 ) 9 9 . 0 . 7 0 . 0 0 5 I = . 5 2 1 T o t a l No. o f A n i m a l s = 5 8 N = K - 2 = 5 No. o f d o s e s K = 7 ( C h i ) 2 = 8 . 2 9 x . 5 2 1 = 4 . 3 2 A n i m a l / d o s e = 8 . 2 9 131 was f o u n d t o be 4 . 3 2 , w h i c h i s l e s s t h a n 1 1 . 1 . T h e r e f o r e t h e r e was n o t s i g n i f i c a n t h e t e r o g e n e i t y i n t h e d a t a . The L D ^ g was 8 0 . 9 m g / K g ; t h e L D ^ Q was 8 6 . 1 m g / K g ; and t h e LDg^ was 9 2 . 3 m g / K g . The s l o p e f u n c t i o n ( S ) was f o u n d t o be 1 . 0 4 . The u p p e r a n d l o w e r l i m i t s f o r t h e 95% c o n f i d e n c e l e v e l was c a l c u l a t e d t o be 8 9 . 3 m g / K g ; a n d 8 3 . 0 m g / K g . T h u s , i t c a n be o b s e r v e d t h a t f o r o u r p a r t i c u l a r v e h i c l e , t h e i n t r a v e n o u s l e t h a l d o s e f o r 50% o f t h e m i c e was 8 6 . 1 mg/Kg ( 8 3 . 0 m g / K g - - 8 9 . 3 m g / K g ) . The 1 0 - b r o m o c a p r i c a c i d i n t h i s p a r t i c u l a r v e h i c l e was v e r y t o x i c as t h e L D ^ Q was o b s e r v e d t o be 8 6 . 1 m g / K g . T h e r e may be an a d d i t i v e o r s y n e r g i s t i c e f f e c t o f t h e p r o p y l e n e g l y c o l a l o n g w i t h t h e b r o m o c a p r i c a c i d . H o w e v e r , when c o n s i d e r e d i n d i v i d u a l l y , t h e h i g h e s t d o s e o f p r o p y l e n e g l y c o l a d m i n i s t e r e d was w e l l b e l o w t h a t o f t h e minimum l e t h a l d o s e ( L a t v e n a n d M o l i t i e r , 1 9 3 9 ) . H o w e v e r , t h i s f o r m u l a was m a i n t a i n e d as an a l t e r a t i o n o f t h e c o m p o n e n t s , l e d t o s e p a r a t i o n o f t h e p h a s e s a n d a m i l k y s o l u t i o n . The t o x i c e f f e c t s w e r e much more p r o m i n e n t w i t h 1 0 - b r o m o -c a p r i c a c i d t h a n w i t h t h e 1 2 - b r o m o l a u r i c a c i d . T w i t c h i n g a n d t r e m o r s w e r e n o t e d t o a c c o m p a n y t h e l o w e s t d o s e c a u s i n g any a d v e r s e e f f e c t s . The m u s c u l a r s y s t e m a p p e a r e d t o be a f f e c t e d a n d t h e a n i m a l o f t e n c o l l a p s e d , a l t h o u g h r e c o v e r y was n o t e d w i t h i n 3 m i n u t e s . As t h e d o s a g e i n j e c t e d was i n c r e a s e d , c o l l a p s e was p r o m i n e n t , a l o n g w i t h m u s c l e r i g i d i t y , p a l p i t a t i o n s , a n d l o s s o f t h e r i g h t i n g r e f l e x . H y p e r n e a a p p e a r e d t o be a c c o m p a n i e d by c h o k i n g , a n d f i n a l l y t o n i c c o n v u l s i o n s w h i c h w e r e f o l l o w e d by d e a t h . 132 The LDgQ r e p o r t e d f o r c a p r i c a c i d was 129 m g „ / K g ( O r o a n d W r e t l i n d , 1 9 6 1 ) . T h i s LDgg was s l i g h t l y h i g h e r t h a n o u r e x p e r i m e n t a l r e s u l t s . The d i s c r e p e n c y c o u l d n o t be a t t r i b u t e d t o s p e c i e s d i f f e r e n c e s , as m i c e w e r e u s e d i n b o t h s t u d i e s . H o w e v e r , t h e a c i d s d i f f e r e d i n a bromo g r o u p , w h i c h c o u l d a t t r i b u t e t o d i f f e r e n c e s i n t h e t o x i c i t y . The m o s t p r o b a b l e r e a s o n f o r t h e d i f f e r e n t L D ^ Q o b t a i n e d a p p e a r e d t o be t h e i n h e r e n t p r o p e r t y o f t h e v e h i c l e . O r o a n d W r e t l i n d ( 1 9 3 9 ) u s e d a 2% e m u l s i o n o f c a p r i c a c i d i n c o t t o n s e e d o i l w h i l e o u r v e h i c l e was a d i s t i n c t l y d i f f e r e n t a q u e o u s s o l u t i o n . The b r o m o a c e t a t e may a l s o h a v e c o n t r i b u t e d t o t h e t o x i c e f f e c t s o f t h e b r o m o c a p r i c a c i d , as p r e v i o u s l y d i s c u s s e d 6 . E x c r e t i o n S t u d i e s The e x c r e t i o n s t u d i e s w e r e p e r f o r m e d t o d e t e r m i n e t h e r a t e a n d t h e r o u t e by w h i c h t h e r a d i o i o d i n a t e d f a t t y a c i d s w e r e e l i m i n a t e d f r o m t h e b o d y . M i c e w e r e i n j e c t e d w i t h . 5 - l . O y C i o f t h e l a b e l e d m a t e r i a l by t a i l v e i n and t h e a c t i v i t y r e m a i n i n g i n t h e b o d y was d e t e r m i n e d by w h o l e body c o u n t i n g u s i n g t h e T u b o r . The u r i n e a n d t h e f e c e s w e r e c o l l e c t e d f o r t h e f i r s t 12 h o u r s a f t e r i n j e c t i o n t o d e t e r m i n e t h e amount e x c r e t e d by e a c h r o u t e . The g e o m e t r y s t u d y done u s i n g t h e T u b o r r e v e a l e d t h a t t h e s h e l f l e v e l as w e l l a s t h e a x i a l p o s i t i o n i n f l u e n c e d t h e c o u n t r a t e s . The h o r i z o n t a l a x i s was d e s i g n a t e d A a n d t h e v e r t i c a l a x i s B . The r e s u l t s a r e as f o l l o w s when a 60 p C i s a m p l e was c o u n t e d f o r 1 . 0 m i n u t e a n d c o r r e c t e d f o r b a c k g r o u n d a c t i v i t y . 133 TABLE . X V I I I The E f f e c t o f . S h e l f L e v e l s a n d A x i a l D i r e c t i o n  On C o u n t R a t e s U s i n g t h e T u b o r Di r e c t i on S h e l f L e v e l CPM (%) A ' 5 . 2 5 9 8 . 4 ' B 5 . 2 5 1 0 0 . 0 A 5 . 5 0 8 4 . 1 B 5 . 5 0 8 5 . 9 A 5 . 7 5 7 6 . 7 B 5 . 7 5 7 7 . 0 A 6 . 0 0 6 5 . 5 B 6 . 0 0 6 5 . 8 A 6 . 2 5 5 9 . 7 B 6 . 2 5 6 0 . 0 A 6.-50 5 6 . 3 B 6 . 5 0 5 7 . 0 A 6 . 7 5 5 3 . 6 B 6 . 7 5 5 4 . 1 A 7 . 0 0 5 3 : 2 B 7 . 0 0 5 2 . 0 A 7 . 2 5 5 2 . 9 B 7 . 2 5 5 2 . 2 A 7 . 5 0 5 3 . 9 B 7 . 5 0 5 4 . 9 I t was a p p a r e n t t h a t a s t h e s h e l f l e v e l was l o w e r e d , t h e c o u n t s p e r m i n u t e d e c r e a s e d a c c o r d i n g l y . C o u n t s o b t a i n e d f r o m s h e l f l e v e l 5 . 2 5 w e r e t h e h i g h e s t o f t h e s h e l f l e v e l s , as w e r e t h e c o u n t s o b t a i n e d i n t h e v e r t i c a l a s o p p o s e d t o t h e h o r i z o n t a l p o s i t i o n . I t was d e c i d e d t o m a i n t a i n t h e s h e l f a t t h e 5 . 2 5 l e v e l a n d u s e t h e v e r t i c a l a x i s f o r p o s i t i o n i n g t h e c o n t a i n e r s f o r t h e w h o l e b o d y c o u n t i n g . 131 W h o l e b o d y c o u n t i n g was c a r r i e d o u t f o r 1-1 a u r i c a c i d , I - c a p r i c a c i d , a n d N a I - 1 3 1 (6% H S A ) . A minimum o f 6 a n d a maximum o f 18 m i c e w e r e u s e d f o r e a c h d a t a p o i n t . The c o u n t s o b t a i n e d w e r e c o r r e c t e d f o r b a c k g r o u n d a c t i v i t y . D u r i n g t h e a n a l y s i s , a n y c o u n t s 134 w h i c h d e v i a t e d i n e x c e s s o f 3 s t a n d a r d d e v i a t i o n s w e r e r e j e c t e d . The mean f o r e a c h g r o u p o f m i c e a t e a c h t i m e i n t e r v a l was c a l c u l a t e d a l o n g w i t h t h e s t a n d a r d d e v i a t i o n a n d t h e s t a n d a r d e r r o r o f t h e m e a n . H o w e v e r , t h e s e c o u n t s w e r e n o t c o r r e c t e d f o r p h y s i c a l d e c a y . The e x c r e t i o n d a t a was e n t e r e d i n t o t h e U . B . C . Amdahl #470 c o m p u t e r a n d a n a l y z e d u s i n g t h e n o n l i n p r o g r a m ( M e t z l e r e t a l . , 1 9 6 4 ) . The n o n l i n p r o g r a m e s t i m a t e s t h e p a r a m e t e r s i n t h e n o n l i n e a r s y s t e m o f e q u a t i o n s u s i n g w e i g h t e d l e a s t s q u a r e s . The d a t a was w e i g h t e d by t h e number o f a n i m a l s p e r t i m e p e r i o d / s t a n d a r d d e v i a t i o n s q u a r e d . a ) 1 3 1 I - C a p r i c A c i d 1 31 The I - c a p r i c a c i d seemed t o be e l i m i n a t e d r a p i d l y f r o m t h e mouse b o d y . A t 3 , 1 2 , a n d 24 h o u r s r e s p e c t i v e l y a f t e r i n t r a v e n o u s i n j e c t i o n s , 4 3 . 7 % , 7 8 . 4 % , a n d 8 7 . 7 % had b e e n e l i m i n a t e d f r o m t h e mouse b o d y . ( i ) C o m p a r t m e n t a l A n a l y s i s I n c o m p u t e r a n a l y s i s , t h e e x c r e t i o n d a t a was a d e q u a t e l y d e s c r i b e d by t h r e e e x p o n e n t i a l s o f t i m e . ( F i g u r e 19) The t r i -e x p o n e n t i a l e q u a t i o n c a n be d e s c r i b e d a s f o l l o w s : C = A e " a t + B e " « 1 + F e _ Y t C = c o n c e n t r a t i o n a t t i m e t A , B , F = Y - i n t e r c e p t s o f t h e e l i m i n a t i o n c u r v e a, e,y = r a t e c o n s t a n t s o f t h e i n d i v i d u a l e x p o n e n t i a l l i n e s The v a l u e s o f A , B , F , a , p , a n d j w e r e p r o v i d e d by t h e c o m p u t e r . H e n c e , t h e e f f e c t i v e t j ( h a l f - l i f e ) f o r e a c h c o m p o n e n t c a n be 135 c a l c u l a t e d by t h e t e r m : t ^ = . 6 9 3 2 ( r a t e c o n s t a n t ) From t h e r e s u l t s , t h e r e a p p e a r e d t o be t h r e e c o m p o n e n t s , a s h o r t l i v e d c o m p o n e n t o f . 9 0 h o u r s , a medium c o m p o n e n t o f 3 . 9 1 h o u r s , a n d a l o n g c o m p o n e n t o f 7 4 . 9 h o u r s . From t h e y - i n t e r c e p t s o f t h e i n d i v i d u a l c o m p o n e n t s f r o m t h e n o n l i n a n a l y s i s , i t a p p e a r e d t h a t a p p r o x i m a t e l y 3 6 . 7 % o f t h e i n j e c t e d d o s e was c l e a r e d a t t h e f a s t e s t r a t e , w h i l e 6 1 . 6 % was c l e a r e d a t t h e medium r a t e , a n d a b o u t 1 4 . 5 % was a c c o u n t e d f o r by t h e t e r m i n a l e l i m i n a t i o n p h a s e . S i n c e t h i s i s a t r i e x p o n e n t i a l c u r v e r e p r e s e n t i n g w h o l e b o d y c o u n t i n g , i t i s v e r y d i f f i c u l t t o i n t e r p r e t w h i c h p r o c e s s e s o f e l i m i n a t i o n e a c h c o m p o n e n t r e p r e s e n t s . W h o l e b o d y c o u n t i n g a c c o u n t s f o r t h e t o t a l a c t i v i t y r e m a i n i n g i n t h e mouse b o d y , r e g a r d l e s s o f t h e d i s t r i b u t i o n . I t a p p e a r s t h a t a s a m i x e d f u n c t i o n , t h e r e i s some c o n t r i b u t i o n f r o m t h e f i r s t c o m p o n e n t t o t h e s e c o n d a n d t h e t h i r d c o m p o n e n t . T h e r e i s a l s o some c o n t r i b u t i o n f r o m t h e s e c o n d c o m p o n e n t t o t h e t h i r d c o m p o n e n t . The f i r s t a n d t h e s e c o n d c o m p o n e n t s may r e p r e s e n t e l i m i n a t i o n by u r i n a r y e x c r e t i o n , s i n c e b o t h t h e s e c o m p o n e n t s h a v e r e l a t i v e l y s h o r t h a l f - l i v e s . T h i s a p p e a r s t o be i n a g r e e m e n t w i t h t h e u r i n a r y e x c r e t i o n d a t a , w h e r e 5 7 . 6 % o f t h e i n j e c t e d a c t i v i t y was r e c o v e r e d i n t h e u r i n e a t 6 h o u r s a f t e r i n j e c t i o n . The t e r m i n a l e l i m i n a t i o n p h a s e may r e p r e s e n t r a d i o a c t i v i t y w h i c h i s b o u n d t i g h t l y t o some t i s s u e a n d i s r e l e a s e d v e r y s l o w l y . T h i s t i g h t l y b o u n d r a d i o -a c t i v i t y may be t h y r o i d a l I o d i d e - 1 3 1 o r p r o t e i n b o u n d i o d i d e . T h i s t h i r d c o m p o n e n t p r o b a b l y r e p r e s e n t s e l i m i n a t i o n by f e c a l e x c r e t i o n a n d o n l y a c c o u n t s f o r a b o u t 14% o f t h e i n j e c t e d d o s e . 136 r 1 0 5 r 9 0 | I i i 1 1 1 1 0 2 0 4 0 6 0 8 0 100 120 Time (minutes) x 162 F i g u r e 19 W h o l e - B o d y E x c r e t i o n o f 1 0 - I o d o d e c a n o i c A c i d A f t e r I n t r a v e n o u s I n j e c t i o n i n M i c e 9 a R a d i o a c t i v i t y l e v e l s h a v e b e e n d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . 137 As d e f i n e d i n b i o p h a r m a c e u t i c s , t h e b i o l o g i c a l h a l f - l i f e i s t h e t i m e r e q u i r e d f o r t h e p l a s m a , s e r u m , o r w h o l e b l o o d t o d r o p t o o n e - h a l f o f i t s v a l u e f o l l o w i n g t h e e s t a b l i s h m e n t o f e q u i l i b r i u m ( R i t s c h e l , 1 9 7 2 ) . The l o s s o f d r u g f r o m p l a s m a , s e r u m , o r b l o o d i s due t o m e t a b o l i s m o r e x c r e t i o n i n t o u r i n e o r f e c e s . H o w e v e r , i n n u c l e a r m e d i c i n e , t h e t e r m b i o l o g i c a l h a l f - l i f e i s u s e d t o d e n o t e t h e t i m e r e q u i r e d by t h e b o d y t o e l i m i n a t e o n e - h a l f o f t h e d o s e o f ' a n y s u b s t a n c e by t h e r e g u l a r p r o c e s s e s o f e l i m i n a t i o n , ( E a r l y e t a l . , 1 9 6 9 ) . F r o m t h e t r i e x p o n e n t i a l 131 w h o l e b o d y e x c r e t i o n c u r v e o f I - c a p r i c a c i d , t h r e e e f f e c t i v e h a l f - l i v e s w e r e c a l c u l a t e d . S i n c e a b i o l o g i c a l h a l f - l i f e i s d e p e n d e n t o n t h e p h y s i c a l h a l f - l i f e a n d t h e e f f e c t i v e h a l f - l i f e , t h e b i o l o g i c a l h a l f - l i f e f o r t h e t e r m i n a l e l i m i n a t i o n p h a s e c a n be c a l c u l a t e d a s f o l l o w s : t ( b i o l ) = \ ( p h y s ) x \ ( e f f ) \ ( p h y s ) - \ ( e f f ) F o f l 3 1 l » ' S ( p h y s ) = 8 ' 0 5 d a y s ^ ( e f f ) = 3 . 1 2 d a y s T h e r e f o r e , t h e t , . -, x c a n be c a l c u l a t e d t o be 5 . 1 1 d a y s . \ ( b i o l ) J ( i i ) U r i n a r y A n a l y s i s From t h e w h o l e b o d y c o u n t i n g d a t a i t was e v i d e n t t h a t t h e i n j e c t e d r a d i o a c t i v i t y was e l i m i n a t e d r a p i d l y f r o m t h e ' . b o d y . A t 24 and 48 h o u r s r e s p e c t i v e l y a f t e r i n t r a v e n o u s a d m i n i s t r a t i o n , o n l y 1 2 . 3 % a n d 9 . 7 2 % o f t h e i n j e c t e d d o s e r e m a i n e d i n t h e b o d y . I n o r d e r t o d e t e r m i n e t h e r o u t e o f e l i m i n a t i o n , t h e u r i n e a n d f e c e s w e r e c o l l e c t e d a n d c o u n t e d s i m u l t a n e o u s l y w i t h t h e m i c e i n o r d e r t o a c c o u n t f o r t o t a l 138 i n j e c t e d a c t i v i t y . P r e p a r e d s t a n d a r d s w e r e a l s o c o u n t e d a t t h e same t i m e 131 s o t h a t d e c a y was n o t n e c e s s a r y . A p p r o x i m a t e l y . 0 2 p C i / g m o f I - c a p r i c a c i d was i n j e c t e d i n t o e a c h m o u s e . The r e s u l t s o f t h e s e u r i n e a n d f e c a l c o l l e c t i o n s a r e shown i n T a b l e 1 9 . ' T a b l e X I X E x c r e t i o n o f ^ I - C a p r i c A c i d i n U r i n e a n d F e c e s o f M i c e 5 Time ( h o u r s ) U r i n e F e c e s B o d y 6 5 7 . 6 2 . 8 0 3 9 . 1 10 7 3 . 0 3 . 8 5 2 9 . 9 24 8 2 . 4 8 . 8 8 1 1 . 8 a The mean o f 3 m i c e c a l c u l a t e d a s a p e r c e n t o f i n j e c t e d d o s e . I t c a n be o b s e r v e d a f t e r 2 4 ' h o u r s t h a t a p p r o x i m a t e l y 9 1 . 3 % o f t h e i n j e c t e d d o s e had b e e n e l i m i n a t e d . O f t h i s , 8 2 . 4 % was e x c r e t e d i n t h e u r i n e a n d 8 . 8 8 % was e x c r e t e d i n t h e f e c e s . The p e r c e n t e x c r e t e d i n t h e f e c e s a p p e a r s t o be h i g h . T h i s c o u l d be due t o - c o n t a m i n a t i o n o f t h e f e c e s w i t h u r i n e . I n o r d e r t o a s c e r t a i n t h e c h e m i c a l s p e c i e s o f t h e r a d i o a c t i v e compound e x c r e t e d , u r i n a r y a n a l y s i s was d o n e . A p p r o x i m a t e l y 10 y l o f e a c h i n d i v i d u a l u r i n e s a m p l e was c h r o m a t o g r a p h e d o n Gelman I T L C - S G s h e e t s a n d d e v e l o p e d i n t h e same s o l v e n t s y s t e m u s e d f o r r a d i o c h e m i c a l p u r i t y o f t h e r a d i o i o d i n a t e d f a t t y a c i d s . F o r c o m p a r i s o n , u r i n e . w a s c o l l e c t e d f r o m c o n t r o l m i c e a n d d i l u t i o n s o f t h e u r i n e w e r e : . m a d e . I n d i v i d u a l s a m p l e s w e r e s p i k e d w i t h N a I - 1 3 1 (6% H S A ) , N a I - 1 3 1 , a n d 139 1 3 1I-capric acid. In addition, mice were injected with NaI-131(6% HSA) and the urine collected. These samples were also spotted and chromato-131 graphed. The I-capric acid spiked urine sample showed values of .93 while the NaI-131, the NaI-131 (6%HSA), as well as the urine collected from the mice injected with Nal (6% HSA) showed Rf values of 0. The free Iodide-131 ion remained at the origin. The chromatogram of the 131 mice injected with I-capric acid showed a spot with a R^  value of 0. This suggested that the excreted radioactivity was in the form of iodide and that presumably the metabolism of the radioiodinated fatty acid resulted in the urinary excretion of the free Iodide-131 as the ion. This data appears to be in agreement with the distribution studies, in which it appeared that the end product of Beta oxidation, iodoacetate, diffused from the myocardium and was subsequently hydrolyzed to free iodide in the blood (Poe et al., 1976; Robinson and Lee, 1975). b) 1 3 1I-Lauric Acid 1 31 The I-il.auric acid was eliminated in a similar manner from 131 the mouse body as the I-capric acid. At 3, 12, and 24 hours respect, tively after injection, 42.2%, 68.2%, and 83.4% had been eliminated from the mouse body. (i) Compartmental Analysis In the same computer analysis as previously described, the excretion curve fitted into a triexponential equation. The effective half-lives of the three components were found to be 1.67 hours, 7.68 hours, and 71.6 hours. It appeared that 46.6% of the injected dose 140 105 [ 9 0 T Time (minutes) F i g u r e 20 W h o l e - B o d y E x c r e t i o n o f 1 2 - I o d o l a u r i c a c i d a f t e r I n t r a v e n o u s I n j e c t i o n i n M i c e a a R a d i o a c t i v i t y l e v e l s h a v e b e e n d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . 1 4 1 was c l e a r e d by t h e f a s t e s t r a t e , 3 8 . 4 % c l e a r e d by t h e medium r a t e , w h i l e 17 .8% was c l e a r e d by t h e s l o w e s t r a t e . 131 I t was a s s u m e d t h a t t h e e l i m i n a t i o n o f t h e I - l a u r i c a c i d 131 w a s - a p p r o x i m a t e l y t h e same a s t h a t o f t h e I - c a p r i c a c i d f r o m t h e s i m i l a r t r i e x p o n e n t i a l c u r v e s . The f i r s t a s w e l l a s t h e s e c o n d c o m p o n e n t p r e s u m a b l y r e p r e s e n t e d a d e c r e a s e i n t h e w h o l e b o d y r a d i o -a c t i v i t y due t o u r i n a r y e x c r e t i o n . T h i s a p p e a r s t o a g r e e w i t h ;,the u r i n a r y e x c r e t i o n d a t a , i n w h i c h 5 3 . 8 % o f t h e i n j e c t e d d o s e was r e c o v e r e d i n t h e u r i n e a t 6 h o u r s a f t e r i n j e c t i o n . The t h i r d c o m p o n e n t p r o b a b l y r e p r e s e n t s e l i m i n a t i o n by f e c a l e x c r e t i o n . The b i o l o g i c a l h a l f - l i f e f o r e a c h c o m p o n e n t c a n be c a l c u l a t e d f r o m t h e e f f e c t i v e h a l f - l i f e , . The 131 e f f e c t i v e h a l f - l i f e f o r I - l a u r i c a c i d f o r t h e t e r m i n a l e l i m i n a t i o n p h a s e was 7 1 . 6 h o u r s . Thus t h e b i o l o g i c a l h a l f - l i f e was c a l c u l a t e d t o be 4 . 7 4 d a y s . ( i i ) U r i n a r y A n a l y s i s Q u a n t i t a t i v e u r i n a r y a n d f e c a l c o l l e c t i o n s w e r e made f o r 131 t h e f i r s t 24 h o u r s f o l l o w i n g i n t r a v e n o u s i n j e c t i o n s o f t h e I - l a u r i c 131 a c i d . A p p r o x i m a t e l y . 0 2 i i j C i / g m o f I - l a u r i c a c i d was i n j e c t e d i n t o e a c h mouse and t h e r e s u l t s a r e shown i n T a b l e 2 0 * . TABLE XX, •' E x c r e t i o n o f ^ I - L a u r i c A c i d i n U r i n e a n d F e c e s o f M i c e 9 Time ( h o u r s ) U r i n e F e c e s B o d y 6 5 3 . 8 5 . 4 8 5 0 . 6 9 6 5 . 5 5 . 7 7 3 7 . 7 12 7 0 . 4 7 . 3 3 3 2 . 6 24 7 8 . 9 9 . 4 1 4 . 5 The mean o f 3 m i c e c a l c u l a t e d a s a p e r c e n t o f i n j e c t e d d o s e ] 42 A t 24 h o u r s a f t e r i n j e c t i o n , 8 8 . 3 % o f t h e i n j e c t e d d o s e had had b e e n e l i m i n a t e d f r o m t h e mouse b o d y . Of t h i s , 7 8 . 9 % was e x c r e t e d v i a t h e u r i n e a n d 9 . 4 % was e x c r e t e d v i a t h e f e c e s . 131 U r i n e s a m p l e s o f m i c e i n j e c t e d w i t h I - l a u r i c a c i d , N a I - 1 3 1 (6% H S A ) , a s w e l l a s u r i n e f r o m a c o n t r o l g r o u p o f m i c e s p i k e d 131 w i t h . I - l a u r i c a c i d a s w e l l a s N a I - 1 3 1 w e r e c h r o m a t o g r a p h e d o n 131 Gelman I T L C - S G a n d c o m p a r e d . The R f v a l u e o f I - l a u r i c a c i d s p i k e d u r i n e was . 9 2 , w h i l e t h e N a I - 1 3 1 s a m p l e s h a d R f v a l u e s o f z e r o . The e x c r e t e d r a d i o a c t i v i t y a p p e a r e d t o be i n t h e f o r m o f i o d i d e - 1 3 1 a s t h e i o n . a ) N a I - 1 3 1 (6% HSA) A s i m i l a r w h o l e body e l i m i n a t i o n c u r v e was c o n s t r u c t e d f r o m t h e d a t a o b t a i n e d a " f t e r i n t r a v e n o u s i n j e c t i o n s o f N a I - 1 3 1 i n 6% human s e r u m a l b u m i n . The human s e r u m a l b u m i n was u s e d o n l y t o p r o v i d e a n i d e n t i c a l v e h i c l e f o r i n t r a v e n o u s i n j e c t i o n p u r p o s e s . The I o d i d e - 1 3 1 a p p e a r e d t o be c l e a r e d more r a p i d l y t h a n t h e r a d i o i o d i n a t e d f a t t y a c i d s . A t 3 and 24 h o u r s r e s p e c t i v e l y p o s t - i n j e c t i o n , t h e p e r c e n t a g e s e l i m i -n a t e d w e r e 5 9 . 1 % a n d 9 0 . 9 % . ( i ) C o m p a r t m e n t a l A n a l y s i s C o m p u t e r a n a l y s i s r e v e a l e d a t r i e x p o n e n t i a l d e c l i n e i n r a d i o a c t i v i t y w i t h i n t h e mouse b o d y w i t h t i m e . The e f f e c t i v e h a l f -l i v e s w e r e e s t i m a t e d t o be 1 . 2 5 h o u r s ( 6 9 . 6 % ) , 6 . 3 8 h o u r s ( 3 3 . 4 % ) , a n d 71,. 1 h o u r s ( 9 . 3 1 % ) . A g a i n , t h e t e r m i n a l e l i m i n a t i o n p h a s e was a s s u m e d t o r e p r e s e n t t h e e l i m i n a t i o n by f e c a l e x c r e t i o n . The b i o l o g i c a l 143 h a l f - l i f e was c a l c u l a t e d t o be 4 . 6 9 d a y s f o r t h e t e r m i n a l e l i m i n a t i o n p h a s e . TABLE XXI 1 31 C o m p a r i s o n o f H a l f - l i v e s f o r I - C a p r i c A c i d 131 I - L a u r i c A c i d , a n d N a I - 1 3 1 (6% H S A ) a 131 S a m p l e I - C a p r i c A c i d \ ( e f f ) ( h o u r s ) 7 4 . 9 8 1 3 1 I - L a u r i c A c i d N a I - 1 3 1 (6% HSA) 7 1 . 5 6 7 1 . 0 9 V 2 ( b i o l ) ( h 0 u r s ) 1 2 2 . 5 1 1 3 . 6 1 1 2 . 5 a H a l f - l i v e s w e r e c a l c u l a t e d u s i n g t h e t e r m i n a l p h a s e o f t h e w h o l e b o d y e x c r e t i o n c u r v e . 131 131 I t was e v i d e n t t h a t t h e I - l a u r i c a c i d , I - c a p r i c a c i d , a s w e l l a s t h e N a I - 1 3 1 (6% HSA) e x h i b i t e d s i m i l a r p r o p e r t i e s i n c o m p a r t m e n t a l a n a l y s i s . ( T a b l e 22:-) TABLE X X I I C o m p a r i s o n o f t h e E f f e c t i v e H a l f - l i v e s a n d t h e P e r c e n t a g e s E l i m i n a t e d S a m p ! e N a I - 1 3 1 by t h e T h r e e C o m p o n e n t s o f t h e E l i m i n a t i o n C u r v e s Component 1 Component 2 Component 3 131 131 I - L a u r i c a c i d I - C a p r i c a c i d 1 . 2 5 h o u r s ( 6 9 . 6 % ) 1 . 6 7 h o u r s ( 4 6 . 6 % ) 0 . 9 0 h o u r s ( 3 6 . 6 % ) 6 . 3 8 h o u r s ( 3 3 . 4 % ) 7 . 6 8 h o u r s ( 3 8 . 4 % ) 3 . 9 1 h o u r s ( 6 1 . 0 % ) 7 1 . 7 h o u r s ( 3 1 . 0 % ) 7 1 . 6 h o u r s ( 1 7 . 8 % ) 7 4 . 9 h o u r s ( 1 4 . 5 % ) 144 100 j-I Time (minutes) xK>2 F i g u r e 2 1 W h o l e - B o d y E x c r e t i o n o f N a I - 1 3 1 ( H S A ) a f t e r I n t r a v e n o u s I n j e c t i o n i n M i c e 3 a R a d i o a c t i v i t y l e v e l s h a v e b e e n d e t e r m i n e d e v e n a f t e r m e t a b o l i s m o f t h e f a t t y a c i d . 145 A l t h o u g h t h e h a l f - l i v e s w e r e s i m i l a r f o r t h e 3 c o m p o n e n t s o f t h e w h o l e b o d y e x c r e t i o n c u r v e , t h e p e r c e n t a g e s a c c o u n t e d f o r by e a c h c o m p o n e n t v a r i e d . T h i s was p a r t i c u l a r l y t r u e o f t h e amount a t t r i b u t e d t o t h e f i r s t c o m p o n e n t . The N a I - 1 3 1 was e l i m i n a t e d much more r a p i d l y t h a n t h e r a d i o i o d i n a t e d f a t t y a c i d s , a s shown by t h e w h o l e b o d y e x c r e t i o n c u r v e as w e l l as t h e c o m p a r t m e n t a l a n a l y s i s . A l a r g e r p o r t i o n o f N a I - 1 3 1 was a c c o u n t e d f o r by t h e f i r s t c o m p o n e n t t h a n f o r 131 131 I - l a u r i c a c i d a n d I - c a p r i c a c i d . T h i s c o u l d p o s s i b l y be d u e t o t h e f a c t t h a t t h e r a d i o a c t i v i t y was a l r e a d y i n t h e i o d i d e i o n f o r m i n t h e b l o o d and t h u s was r e a d i l y a v a i l a b l e f o r r e n a l e x c r e t i o n w h i l e t h e r a d i o i o d i n a t e d f a t t y a c i d s had t o u n d e r g o m e t a b o l i s m p r i o r t o r e n a l e x c r e t i o n . A l t h o u g h t h e e f f e c t i v e h a l f - l i v e s f o r t h e f i r s t two c o m p o n e n t s v a r i e d , i t was e x p e c t e d a s t h e m i c e e x c r e t e d v e r y c o n c e n t r a t e d u r i n e a n d i t was d i f f i c u l t t o i n d u c e t h e m i c e t o u r i n a t e . On . v o i d i n g , t h e w h o l e body c o u n t s c o u l d d e c r e a s e f r o m 2 0 - 3 0 % . A l a r g e r p o r t i o n o f t h e r a d i o a c t i v i t y was a t t r i b u t e d t o t h e t h i r d c o m p o n e n t f o r N a I - 1 3 1 t h a n f o r t h e r a d i o i o d i n a t e d f a t t y a c i d s . T h i s c o m p o n e n t was p r e s u m a b l y due t o t i g h t l y b o u n d i o d i d e . T h i s c o m p a r t m e n t may c o n c e i v a b l y i n c l u d e t h e u p t a k e by t h e t h y r o i d o r b i n d i n g t o p l a s m a p r o t e i n s . A g a i n , t h e r e a s o n f o r t h e l a r g e r amount b e i n g a c c o u n t e d f o r by t h e t h i r d c o m p o n e n t c o u l d be due t o t h e a v a i l a b i l i t y o f t h e f r e e i o d i d e i o n f o r u p t a k e by t h e t h y r o i d a n d b i n d i n g t o t h e p r o t e i n s . 146 d) C a l c u l a t i o n o f t h e R e n a l H a l f - l i f e F r o m t h e r a d i o a c t i v i t y e x c r e t e d i n t h e c o l l e c t e d u r i n e s a m p l e s , a u r i n a r y e x c r e t i o n c u r v e was c o n s t r u c t e d . From t h i s d a t a , t h e e f f e c t i v e h a l f - l i f e i n t h e k i d n e y was f o u n d t o be 4 . 8 h o u r s f o r t h e p o o l e d r e s u l t s f r o m t h e u r i n e s a m p l e s . T h i s v a l u e was i n a g r e e m e n t w i t h t h e r e n a l h a l f - l i f e o f 4 . 4 3 h o u r s ( K e a t i n g e t a l . , , 1 9 4 7 ) a n d 4 . 4 6 h o u r s ( B e r s o n e t a l . , 1 9 5 2 ) c a l c u l a t e d f r o m human s t u d i e s a f t e r o r a l l y a d m i n i s t e r e d N a I - 1 3 1 . M c C o n a h e y e t a l . ( 1 9 5 1 ) f o u n d t h e r e n a l r a t e - 3 -1 f a c t o r t o be 2 . 0 2 x 10 m i n f r o m w h i c h t h e e f f e c t i v e h a l f - l i f e was c a l c u l a t e d t o be 5 . 7 1 d a y s . The r e n a l h a l f - l i f e c a n be c a l c u l a t e d t o b e 7 . 6 5 d a y s f r o m t h e u r i n a r y e x c r e t i o n r a t e c o n s t a n t s f o u n d by O d d i e e t a l . ( 1 9 5 5 ) . I t c a n be s e e n t h a t t h e r e n a l h a l f - l i v e s w e r e s i m i l a r f o r t h e r a d i o i o d i n a t e d f a t t y a c i d s a n d t h e o r a l l y a d m i n i s t e r e d N a I - 1 3 1 . T h i s c a n p r o b a b l y be a t t r i b u t e d t o t h e r a p i d m e t a b o l i s m o f t h e r a d i o -i o d i n a t e d f a t t y a c i d s , l i b e r a t i n g i o d o a c e t a t e i n t o t h e b l o o d s t r e a m ( R o b i n s o n a n d L e e , 1 9 7 5 ) . Once i n t h e b l o o d , t h e i o d o a c e t a t e i s h y d r o l y z e d t h u s r e l e a s i n g t h e f r e e i o d i d e i o n ( P o e e t a l . , 1 9 7 6 b ) . T h u s , t h e b i o t l o g i c a l b e h a v i o r o f t h e r a d i o i o d i n a t e d f a t t y a c i d s a p p e a r t o be s i m i l a r t o t h a t o f t h e I o d i d e - 1 3 1 i o n a f t e r an i n i t i a l p e r i o d o f m e t a b o l i s m . 147 7 . The R a d i o n u c l i d e S c a n s u s i n g t h e S e a r l e Gamma Camera R a d i o n u c l i d e s c a n s w e r e p e r f o r m e d u s i n g t h e S e a r l e Gamma C a m e r a a t s e l e c t e d t i m e i n t e r v a l s a f t e r i n t r a v e n o u s i n j e c t i o n o f t h e r a d i o l a b e l e d 131 131 c o m p o u n d s . S e r i a l s c a n s w e r e done u s i n g I - c a p r i c a c i d , I - l a u r i c a c i d , N a I - 1 3 1 (6% H S A ) , and T h a l l i u m = 2 0 1 . a) 1 3 1 I - C a p r i c A c i d The f i r s t s e r i e s o f s c a n s a r e shown i n F i g u r e 22 and g i v e s a 131 v i s u a l d i s p l a y o f t h e d i s t r i b u t i o n o f I - c a p r i c a c i d w i t h i n t h e r a b b i t body w i t h t i m e . The i m a g e s d e p i c t e d i n F i g u r e 22 w e r e r e c o r d e d i m m e d i a t e l y a f t e r i n j e c t i o n , 4 m i n u t e s a f t e r i n j e c t i o n , and 8 m i n u t e s a f t e r i n j e c t i o n . The i m m e d i a t e s c a n t a k e n j u s t a f t e r t h e a d m i n i s t r a t i o n 131 o f I - c a p r i c a c i d s h o w e d a c t i v i t y i n t h e l i v e r , h e a r t a n d t h e l u n g s a l t h o u g h t h e s e o r g a n s w e r e d i f f i c u l t t o d i s t i n g u i s h f r o m one a n o t h e r : The 4 m i n u t e s c a n d i s p l a y e d a p r o m i n e n t i m a g e o f t h e l i v e r . The h e a r t a r e a was l e s s p r o n o u n c e d . Images o f t h e k i d n e y s a n d t h e b l a d d e r w e r e f a i n t b u t r e c o g n i z a b l e . I n t h e 8 m i n u t e s c a n , t h e b a c k g r o u n d a c t i v i t y a p p e a r e d t o h a v e i n c r e a s e d as t h e o u t l i n e o f t h e r a b b i t b o d y became a p p a r e n t . The l i v e r i m a g e was s t i l l d i s c e r n i b l e b u t t h e h e a r t s h o w e d a m a r k e d d e c r e a s e i n a c t i v i t y . The r i g h t a n d t h e l e f t k i d n e y i m a g e s w e r e more a p p a r e n t and t h e b l a d d e r i m a g e was o b s e r v e d . T h e s e s c a n s s u p p o r t t h e d i s t r i b u t i o n s t u d i e s done i n m i c e w h i c h i n d i c a t e d t h a t maximum a c t i v i t y i n t h e h e a r t o c c u r s i m m e d i a t e l y a f t e r 131 i n j e c t i o n o f t h e I - C a p r i c a c i d . 149 b) ' J I I - L a u r i c A c i d 131 S c a n s w e r e p e r f o r m e d f o r I - l a u r i c a c i d i m m e d i a t e l y f o l l o w i n g i n j e c t i o n a n d a t 5 , 10 a n d 15 m i n u t e s a f t e r i n j e c t i o n . ( F i g u r e 2 3 ) 131 The r e s u l t s w e r e s i m i l a r t o t h o s e o b s e r v e d f o r I - c a p r i c a c i d . The i m m e d i a t e s c a n s h o w e d d e f i n i t e a c t i v i t y i n t h e a r e a o f t h e h e a r t a n d t h e l i v e r a l t h o u g h t h e i n f e r i o r b o r d e r o f t h e h e a r t c o u l d n o t be d i f f e r e n t i a t e d f r o m t h e l i v e r . I n a d d i t i o n , t h e r e was p r o b a b l y some c o n t r i b u t i o n f r o m t h e r a d i o a c t i v i t y i n t h e l u n g s . The l e f t k i d n e y i m a g e was a l s o f a i n t l y v i s i b l e . I n t h e 5 m i n u t e s c a n t h e h e a r t i m a g e was v a g u e . The k i d n e y s w e r e more p r o n o u n c e d a n d t h e b a c k g r o u n d a c t i v i t y a p p e a r e d t o h a v e i n c r e a s e d w i t h t i m e . I n t h e 10 m i n u t e s c a n t h e l i v e r i m a g e was s t i l l n o t i c e a b l e . The h e a r t a p p e a r e d t o h a v e l o s t m o s t o f t h e a c t i v i t y and was p r e s e n t e d as a f a i n t i m a g e . The b l a d d e r a c t i v i t y was e v i d e n t i n t h e 15 m i n u t e s c a n . The k i d n e y i m a g e s w e r e v e r y p r o m i n e n t and t h e l i v e r a p p e a r e d t o c o n t a i n a s u b s t a n t i a l amount o f a c t i v i t y . The h e a r t a c t i v i t y d i m i n i s h e d w i t h t i m e a n d was i n d i s t i n g u i s h a b l e by 15 m i n u t e s . c ) Na I - 131 .(6% HSA) The s c a n s f o r i n j e c t e d N a I - 1 3 1 i n 6% HSA a r e d e p i c t e d i n F i g u r e 2 4 . The s c a n s w e r e t a k e n i m m e d i a t e l y a f t e r i n j e c t i o n , a n d a t i n t e r v a l s o f 5 , 10 a n d 15 m i n u t e s a f t e r i n j e c t i o n . I n t h e i m m e d i a t e s c a n , b o t h k i d n e y i m a g e s w e r e a l r e a d y v i s i b l e as c o n t r a s t e d t o t h e s c a n s o f t h e r a d i o i o d i n a t e d f a t t y a c i d s , i n w h i c h t h e k i d n e y s became v i s i b l e w i t h t h e p a s s a g e o f t i m e a f t e r t h e i n j e c t i o n . T h e r e was a p p a r e n t u p t a k e by t h e l i v e r , t h e h e a r t a n d p r o b a b l y t h e l u n g s . The 150 F i g u r e 23 S e r i a l S c a n s o f I - L a u r i c A c i d ( A n t e r i o r P r o j e c t i o n i n R a b b i t ) a = I m m e d i a t e b = 5 m i n u t e s c = 10 m i n u t e s d = 15 m i n u t e s 151 F i g u r e 24 S e r i a l S c a n s o f N a I - 1 3 1 (6% HSA) ( A n t e r i o r P r o j e c t i o n i n R a b b i t ) a = I m m e d i a t e c = 10 m i n u t e s b = 5 m i n u t e s d = 15 m i n u t e s 152 b a c k g r o u n d a c t i v i t y a p p e a r e d s l i g h t l y h i g h e r t h a n t h a t o b s e r v e d f o r t h e r a d i o i o d i n a t e d f a t t y a c i d s . I n t h e 5 m i n u t e c s c a n , t h e a c t i v i t y i n t h e h e a r t h a d d i m i n i s h e d c o n s i d e r a b l y . The l i v e r i m a g e a n d t h e k i d n e y i m a g e s w e r e s t i l l v i s i b l e . The b l a d d e r i m a g e was i n c r e a s i n g i n i n t e n s i t y . T h e r e a l s o a p p e a r e d t o b e some a c t i v i t y o b s e r v e d i n t h e h e a d r e g i o n . I n t h e 10 a n d 15 m i n u t e s c a n , t h e b a c k g r o u n d a c t i v i t y i n c r e a s e d . T h e r e a p p e a r e d t o be some u p t a k e o f a c t i v i t y by t h e m u s c l e s . The k i d n e y i m a g e s w e r e p r o n o u n c e d a n d t h e h e a r t i m a g e was i n d i s t i n g u i s h a b l e f r o m t h e b a c k g r o u n d . d) T h a l l i u m - 201 The T h a l l i u m - 201 s c a n was done a t 15 m i n u t e s a f t e r i n t r a v e n o u s i n j e c t i o n . T h e r e a p p e a r e d t o be s i g n i f i c a n t l y l e s s a c t i v i t y i n t h e l i v e r , t h u s t h e h e a r t i m a g e was more d e f i n i t i v e on t h e s c a n . The a c t i v i t y i n t h e k i d n e y was p r o m i n e n t a n d t h e r e was a f a i n t o u t l i n e o f t h e r a b b i t b o d y . e ) C o m p a r i s i o n o f t h e R a d i o n u c l i d e S c a n s 131 131 The I - c a p r i c a c i d a n d t h e I - l a u r i c a c i d d i d n o t a p p e a r t o be g o o d m y o c a r d i a l s c a n n i n g a g e n t s a l t h o u g h t h e r e a p p e a r e d t o be d e f i n i t e u p t a k e by t h e h e a r t . B o t h o f t h e r a d i o i o d i n a t e d f a t t y a c i d s a p p e a r e d t o be i n f e r i o r t o T h a l l i u m - 2 0 1 , t h e p r e s e n t m y o c a r d i a l a g e n t o f c h o i c e f o r c o l d - s p o t i m a g i n g . I t m u s t be n o t e d t h a t t h e e x p e r i m e n t a l s c a n s o b t a i n e d w e r e done w i t h I o d i n e - 1 3 1 as t h e r a d i o a c t i v e l a b e l . I f I o d i n e - 123 h a d been a v a i l a b l e , u n d o u b t e d l y t h e q u a l i t y o f t h e s c a n s w o u l d h a v e b e e n s u p e r i o r . The r a b b i t s w e r e n o t p r e t r e a t e d p r i o r t o a d m i n i s t r a t i o n 153 F i g u r e 25 T h a l l i u m - 201 S c a n i n R a b b i t ( A n t e r i o r p r o j e c t i o n a t 15 m i n u t e s ) 154 o f t h e r a d i o i o d i n a t e d f a t t y a c i d s . T h e m y o c a r d i a l u p t a k e o f t h e r a d i o i o d i n a t e d f a t t y a c i d s c o u l d h a v e b e e n e n h a n c e d . b y t h e s i m u l t a n e o u s a d m i n i s t r a t i o n o f g l u c o s e a n d i n s u l i n t o p r o m o t e s t o r a g e o f t h e r a d i o i o d i n a t e d f a t t y a c i d s a n d t o p r e v e n t B e t a O x i d a t i o n ( G u n t o n e t a l . , 1 9 6 5 ) . I n o u r e x p e r i m e n t a l s c a n s , no b a c k g r o u n d s u b t r a c t i o n was done a n d no a t t e m p t was made t o e n h a n c e t h e s c a n by m a g n i f y i n g t h e c o u n t s o b t a i n e d i n t h e h e a r t . Poe e t a l . ( 1 9 7 6 b ) o b t a i n e d s c a n s 123 u s i n g I - h e x a d e c e n o i c a c i d i n j e c t e d i n t r a v e n o u s l y i n t o m o n g r e l dogs p r e v i o u s l y s u b j e c t e d t o c o r o n a r y l i g a t i o n . The s c a n s w e r e p e r f o r m e d 1 2 3 3 m i n u t e s a f t e r a d m i n i s t r a t i o n o f t h e I - h e x a d e c e n o i c a c i d u s i n g a Pho/Gamma HP S c i n t i l l a t i o n c a m e r a w i t h a p i n h o l e c o l l i m a t o r . The c o l l i m a t o r was p l a c e d 6 - 1 0 cm f r o m t h e c h e s t , a ; d i s t a n c e . . ' e s t i m a t e d t o p r o v i d e a m a g n i f i c a t i o n f a c t o r o f 2 . The d a t a was f u r t h e r a n a l y z e d f o r s u b s e q u e n t b a c k g r o u n d c o r r e c t i o n a n d an a d d i t i o n a l t w o f o l d m a g n i f i c a t i o n . The b a c k g r o u n d v a l u e was u n i f o r m l y s u b t r a c t e d f r o m t h e f i n a l i m a g e . S u b s e q u e n t l y , Poe e t a l . ( 1 9 7 7 b ) p e r f o r m e d c l i n i c a l s t u d i e s i n p a t i e n t s u n d e r g o i n g c a r d i a c c a t h e r i z a t i o n u s i n g t h e same s p e c i f i c a t i o n s as m e n t i o n e d a b o v e . Good q u a l i t y s c a n s w e r e o b t a i n e d i n 3 m i n u t e s i n human s u b j e c t s . The q u a l i t y o f t h e s c a n s o b t a i n e d by Poe e t a l . , 131 ( 1 9 7 6 b , 1 9 7 7 b ) w e r e s u p e r i o r t o o u r s c a n s o b t a i n e d w i t h I - c a p r i c 131 a c i d a n d I - l a u r i c a c i d . H o w e v e r , i t w o u l d be u n j u s t t o c o m p a r e t h e s c a n s as a s u p e r i o r r a d i o i s t o p e , d i f f e r e n t a n i m a l s p e c i e s , a n d a d i f f e r e n t i m a g i n g s y s t e m was u s e d by Poe e t a l . ( 1 9 7 6 b , 1977b) c . I n a d d i t i o n , t h e q u a l i t y o f o u r e x p e r i m e n t a l s c a n s w o u l d h a v e i m p r o v e d 155 w i t h m a g n i f i c a t i o n a n d b a c k g r o u n d c o r r e c t i o n . 8 . D o s i m e t r y The u l t i m a t e a i m o f t h i s s t u d y was t o p e r f o r m m y o c a r d i a l s c a n s 123 u s i n g I - l a b e l e d f a t t y a c i d s . H o w e v e r , due t o some p r o d u c t i o n p r o b l e m s , t h e I o d i n e - 1 2 3 was n o t a v a i l a b l e b u t i t was d e c i d e d t o c a l c u l a t e t h e 1 2 3 r a d i a t i o n d o s i m e t r y f o r I - l a b e l e d f a t t y a c i d s . The r a d i a t i o n d o s e s w e r e c a l c u l a t e d f o r t h e w h o l e b o d y , l i v e r , k i d n e y s , m u s c l e a n d h e a r t . The f o l l o w i n g a s s u m p t i o n s w e r e made f o r t h e d o s e c a l c u l a t i o n s : ( 1 ) The d i s t r i b u t i o n a n d e x c r e t i o n d a t a d e t e r m i n e d i n m i c e a l s o a p p l i e d t o h u m a n s . ( 2 ) The w h o l e b o d y e x c r e t i o n c o m p l i e d w i t h t h e w h o l e b o d y e x c r e t i o n c u r v e . ( 3 ) The u r i n a r y e x c r e t i o n c o l l e c t i o n s w e r e v a l i d , a n d t h e r e n a l b i o l o g i c a l h a l f - l i f e was 4 . 9 2 h o u r s . The e f f e c t i v e 123 h a l f - l i f e c a n be c a l c u l a t e d t o be 3 . 5 7 h o u r s f o r I - l a b e l e d f a t t y a c i d s . ( 4 ) The l i v e r a n d t h e m u s c l e f o l l o w e d t h e f i r s t two c o m p o n e n t s o f t h e w h o l e b o d y e x c r e t i o n c u r v e . ( 5 ) The b l a d d e r a n d t h e h e a r t c o n t r i b u t i o n s t o t h e a b s o r b e d d o s e w e r e n e g l e c t e d b e c a u s e a p p r o p r i a t e v a l u e s h a v e n o t b e e n p u b l i s h e d . 1 23 ( 6 ) The d i s t r i b u t i o n a n d b i o l o g i c a l h a l f - l i f e o f I - l a b e l e d 131 f a t t y a c i d s w i l l be t h e same a s t h e I - l a b e l e d f a t t y a c i d s . 156 The a b s o r b e d d o s e s w e r e c a l c u l a t e d u s i n g t h e e q u a t i o n p r o p o s e d by L o e v i n g e r a n d Berman ( 1 9 6 8 ) a n d m o d i f i e d by S n y d e r e t a l . ( 1 9 7 5 ) D = (r-j *• r 2 ) = A 2 E ^ (r-| +• r 2 ) r a d s mT a. = A 2 z A i f i ( r 1 -s- r 2 ) r a d s Where A 2 = The c u m u l a t e d a c t i v i t y i n s o u r c e o r g a n r 2 ( y C i - h) D (r-j -«- r 2 ) = The mean a b s o r b e d d o s e t o a t a r g e t o r g a n r-j f r o m a r a d i o n u c l i d e d i s t r i b u t e d u n i f o r m l y i n a s o u r c e o r g a n r 2 > ( r a d s ) A . = t h e e q u i l i b r i u m d o s e c o n s t a n t f o r r a d i a t i o n o f t y p e i = l , 2 , 3 , 4 w i t h a f r a c t i o n a l f r e q u e n c y n^ p e r d i s i n t e g r a t o n , a n d a mean e n e r g y E. I n MeV. ; = 2 . 1 3 n^ E i ( g - r a d s ) m-j = t h e mass o f t h e t a r g e t o r g a n r^ ( g ) ot.j (r j r 2 ) = The a b s o r b e d d o s e f r a c t i o n o f e n e r g y f o r t a r g e t o r g a n , r ^ f o r p a r t i c l e s i e m i t t e d i n s o u r c e o r g a n r 2 . $ i ( r i + r 2 ) = The s p e c i f i c a b s o r b e d f r a c t i o n o f e n e r g y f o r t a r g e t o r g a n r-j, f o r p a r t i c l e s i e m i t t e d i n s o u r c e o r g a n r 2 > 157 M o s t o f t h e b i o l o g i c a l d a t a n e e d e d f o r t h e e s t i m a t i o n o f d o s e a. a r e e m b o d i e d i n t h e c u m u l a t i v e a c t i v i t y A 2 , w h i l e t h e r e m a i n i n g p o r t i o n i n v o l v e s p h y s i c a l a n d a n a t o m i c d a t a . ( S n y d e r e t a l . 1 9 7 5 ) . T h u s , S ( r 1 «- r* 2)=E A i $ . ( r iK' 1 The b i o l o g i c a l d a t a u s e d i n e s t i m a t i n g d o s e r e l a t e o n l y t o t h e a n t h r o p o m o r p h i c model u s e d ( s i z e , s h a p e , d e n s i t y , a n d c o m p o s i t i o n ) a n d t o t h e d i s t r i b u t i o n and r e t e n t i o n o f t h e r a d i o n u c l i d e i n s o u r c e o r g a n >"2. V a l u e s o f S u s e d w e r e o b t a i n e d f r o m S n y d e r e t i a l . , ( 1 9 7 5 ) . The a v e r a g e d o s e c a n be c a l c u l a t e d a s : D (r1 <- r 2 ) = A 2 S ( :r 1 «- r 2 J S i n c e t h e r e a r e g e n e r a l l y a number o f s o u r c e o r g a n s , t h e t o t a l a v e r a g e d o s e t o t a r g e t o r g a n r 2 i s D ( r 9 ) = E D ( r r + - r . 9 ) :£ A 2 S ( r 1 <- r 2 ) r t 2 -At. V Where x. = X e f f . 123 1 2 3 a ) T h e o r e t i c a l A b s o r b e d D o s e s f r o m I - c a p r i c o r I - L a u r i c A c i d s ( i ) W h o l e B o d y D o s i m e t r y The v a l u e s f o r ' S ' f o r I o d i n e - 1 2 3 , a s s u m i n g u n i f o r m d i s t r i b u t i o n i n t h e w h o l e b o d y , a r e f r o m S n y d e r e t a l . ( 1 9 7 5 ) . The r e s u l t s a r e b a s e d upon a 6 9 , 8 8 0 g s t a n d a r d b o d y w e i g h t . The a d m i n i s t e r e d 158 133 J1 I • T • *>.4 3 61 0.10 00 .ao 123, I 19h IODINE123 I captvr»-2 eaptwr»-3 Bectron c a p M * - 4 f 7 . C M H - 1 t 9 . C a G * % / a H - T r a m l r i o n • t fag ro - anargy O M w r w c U o r l a d l o M e n Men (M»V) ^ a f o m t m 2 . 0 J 2 0 .5 0 7 1 O J 0 7 8 1.05 0 . 1 5 9 0274 0 4 4 2 0 . 4 3 6 0 . 5 0 4 0 . 5 3 0 0 . 1 4 0 . 1 6 0 . 4 4 0 .28 2 . < 0 . 1 A f o w a d A l l e w a d A f a w c d M l , o x - 0 .161 m, K / ( l + M) - 6.6 towiil a l l wncomrartad A a w m c d a l l wncanvarrad A — w a d a l l wieonvartwd A i w i m d a l l unconvarted | « f , ffectoor Dote Short. , 6 0 - 6 - 6 3 . 6 0 - 6 - 7 1 (T) - TkaoraMcal in fcu . 123 a F i g u r e 26 D e c a y Scheme o f I o d i n e ' ( f r o m D i l l m a n ) 159 d o s e was 2 mCi o f r a d i o i o d i n a t e d f a t t y a c i d . 131 131 The A e f f e c t i v e f o r I - c a p r i c a n d I - l a u r i c a c i d w e r e s u p p l i e d by c o m p u t e r c o m p a r t m e n t a l a n a l y s i s . From t h i s , t h e A b i o l o g i c a l c a n be c a l c u l a t e d . w h e r e : A e f f - A = A. p b A e f f = e f f e c t i v e d e c a y c o n s t a n t = p h y s i c a l d e c a y c o n s t a n t A^ = b i o l o g i c a l d e c a y c o n s t a n t (1) 1 3 1 I - C a p r i c A c i d A '• f o r 1 3 1 1 = . 0 0 3 5 8 7 h " 1 P A-, e f f = . 7 7 0 9 h " 1 A l k = . 7 6 7 3 h " 1 1 - j C I ) - . / / U 3 M l b A 2 e f f = . 1 7 7 4 h " 1 A 2 b = . 1 7 3 8 h " 1 A 3 e f f = . 0 0 9 1 9 h " 1 A 3 b = . 0 0 5 6 h " 1 1 23 The b i o l o g i c a l d e c a y c o n s t a n t f o r I - c a p r i c a c i d w o u l d be t h e s a m e . T h e r e f o r e t h e th b i o l o g i c a l {thb) c a n be c a l c u l a t e d t o b e : thb = . 6 9 3 X b th,^u = - 9 0 3 2 h (Db th(2)b = 3 . 9 8 7 h th{3)h = 1 2 3 . 7 ' . 160 1 ?3 F o r J I - C a p r i c A c i d th e f f thb x t*Sp thp = 1 3 . 0 h = 'thh + t V 2 „ e f f t % ( 2 ) e f f t i s ( 3 ) ' • e f f A = A . i Where al . 8 4 4 5 h 3 . 0 5 1 h t h e i n i t i a l v a l u e o f i e x p o n e n t i a l c o m p o n e n t o f t h e i o d i n e t h a t a p p e a r s t h e s o u r c e . The c u m u l a t e d a c t i v i t y i n t h e w h o l e b o d y i s 11215 y>Ci - h . D = E A 2 S{r} +• r 2 ) w h e r e S = 3 . 1 x 1 0 " 6 r a d | y C i - h . . 0 3 4 7 6 r a d / 2mCi 3 4 . 7 6 m r a d / 2mCi ( 2 ) 1 3 1 I - L a u r i c A c i d x b i o l o g i c a l th b i o l x ] b = . 4 1 1 6 h " 1 t } | ( l ) b = 1 , 6 8 4 h A 9 h = . 0 8 6 6 1 h " 1 th',.n\u = 8 . 0 0 1 h l 2 b " • u o o ° l " ^ 2 ( 2 ) b ^ 3 b = . 0 0 6 0 9 8 h " 1 t i s ( 3 ) b 161 F o r 123 I - L a u r i e A c i d th e f f = thb x t t p = 1 3 . th e f f t > 2 ( 1 ) e f f = 1 . 4 9 1 h e f f , = 4 . 9 5 3 h t J a ( 3 ) e f f = 1 1 . 6 7 h The C u m u l a t e d a c t i v i t y i n t h e w h o l e b o d y A w B = - A o E ] - 4 4 ^ a h J = 13461 y C i - h D E A 2 S (r-j r 2 ) w h e r e S = 3 . 1 x 1 0 " ° r a d / y C i - h D = . 0 4 1 7 3 r a d / 2 m C i = 4 1 . 7 3 m r a d , / 2mCi 162 TABLE X X I I I S , A b s o r b e d Dose U n i t C u m u l a t e d A c t i v i t y  ( r a d / i i C i = h r ) a T a r g e t O r g a n S o u r c e O r g a n W h o l e b o d y L i v e r K i d ney M u s c l e iii v e r 3 . 4 x l 0 " 6 7 . 9 x l 0 " 5 5 . 1 x l 0 " 6 1 . 5 x l 0 " 6 K i dney 3 . 3 x l 0 " 6 5 . I x l O " 6 3 . 4 x l 0 " 4 2 . 0 x l 0 " 6 M u s c l e 2 . 9 x l 0 " 6 1 . 5 x l 0 " 6 2 . 0 x l 0 " 6 4 . 4 x 1 0 " 6 a F r o m S n y d e r e t a l . , 1975 ( i / i ) The C u m u l a t e d A c t i v i t y D = E A 2 S ( r 1 - H r 2 ) A = Ao E 1 . 4 4 th e f f ahj w h e r e h j = t h e i n i t i a l v a l u e o f t h e i * ' 1 e x p o n e n t i a l c o m p o n e n t o f the' i o d i n e t h a t a p p e a r s i n t h e s o u r c e (1) 1 2 3 I - C a p r i c A c i d A w g = C u m u l a t e d a c t i v i t y i n t h e w h o l e b o d y p e r 2mCi a d m i n i s t e r e d . • = 11215 p C i - h A^ = C u m u l a t e d a c t i v i t y i n t h e k i d n e y s p e r 2mCi a d m i n i s t e r e d . i A maximum o f 2 . 6 9 7 % o f t h e i n j e c t e d d o s e was c o n c e n t r a t e d i n t h e k i d n e y . T h e e f f e c t i v e h a l f - l i f e o f 1 2 3 1 - C a p r i c a c i d i n t h e k i d n e y s c a n be c a l c u l a t e d t o be 3 . 5 7 h o u r s . = 2 7 7 . 3 y C i - h 163 A. = C u m u l a t e d a c t i v i t y i n t h e l i v e r p e r 2mCi a d m i n i s t e r e d . The d i s a p p e a r a n c e o f r a d i o a c t i v i t y f r o m t h e l i v e r p r e s u m a b l y c o m p l i e s w i t h t h e f i r s t and t h e s e c o n d c o m p o n e n t o f t h e w h o l e body e x c r e t i o n c u r v e f o r ^ 3 1 j _ c a p r - j c a c i d . A maximum o f 9 . 1 2 9 % o f t h e i n j e c t e d d o s e c o n c e n t r a t e d i n t h e l i v e r . = 5 7 5 . 5 y C i - h A „ = C u m u l a t e d a c t i v i t y i n t h e m u s c l e p e r 2mCi a d m i n i s t e r e d . The d i s a p p e a r a n c e o f r a d i o a c t i v i t y f r o m t h e m u s c l e p r e s u m a b l y c o m p l i e s w i t h t h e f i r s t a n d t h e s e c o n d c o m p o n e n t o f t h e w h o l e b o d y e x c r e t i o n c u r v e . A maximum o f 1 6 . 2 6 % o f t h e i n j e c t e d d o s e c o n c e n t r a t e d i n t h e m u s c l e . = 1 0 2 5 . 2 y C i - h ( 2 ) ' ^ I - L a u r i c A c i d A w B = C u m u l a t e d a c t i v i t y i n t h e w h o l e body p e r 2mCi a d m i n i s t e r e d . . = 13461 y C i - h • = C u m u l a t e d a c t i v i t y i n t h e k i d n e y s p e r 2mCi a d m i n i s t e r e d , k A maximum o f 4 . 0 6 9 % o f t h e i n j e c t e d d o s e c o n c e n t r a t e d i n t h e k i d n e y s . . = 4 1 8 . 4 y C i - h a, A, = C u m u l a t e d a c t i v i t y i n t h e T i v e r p e r 2mCi a d m i n i s t e r e d . T h e . d i s a p p e a r a n c e o f r a d i o a c t i v i t y f r o m t h e l i v e r p r e s u m a b l y c o m p l i e s w i t h t h e f i r s t a n d t h e s e c o n d c o m p o n e n t o f t h e w h o l e b o d y e x c r e t i o n c u r v e f o r ' 3 ' i - l a u r i c a c i d . A maximum o f 2 2 . 8 0 % o f t h e i n j e c t e d d o s e was c o n c e n t r a t e d i n t h e l i v e r . = 1705 y C i - h A M = C u m u l a t e d a c t i v i t y i n t h e m u s c l e p e r 2mCi a d m i n i s t e r e d . T h e d i s a p p e a r a n c e o f r a d i o a c t i v i t y f r o m t h e m u s c l e 164 p r e s u m a b l y c o m p l i e s w i t h t h e f i r s t a n d s e c o n d c o m p o n e n t o f t h e w h o l e b o d y e x c r e t i o n c u r v e . A maximum o f 2 9 . 2 8 % o f t h e i n j e c t e d d o s e was c o n c e n t r a t e d i n t h e l i v e r . 2190 y : C i - h ( i i i ) The Mean Dose (1) 1 2 3 I - C a p r i c A c i d 193 C a l c u l a t i o n o f Mean Dose t o t h e K i d n e y s f o r I - c a p r i c a c i d a. D = Z A 2 S ( r , r 2 ) D k = A w B S ^ K i d n e y s *~ W h o l e B o d y ^ + A k s ( K i d n e y ^ " K i d n e y ) + AjJ> ( K i d n e y L i v e r ) + ^ ( K i d n e y <- M u s c l e ) = . 1 3 6 3 r a d / 2 m C i = 1 3 6 . 3 m r a d / 2mCi C a l c u l a t i o n o f Mean Dose t o t h e L i v e r D = E A 2 S ( r ] ^ r 2 ) D = \B s C - i v e r " * " W h o l e B o d y ) + A L S ( L i v e r L i v e r ) + A^S ( L i v e r s K i d n e y ) + A^ S ( L i v e r « - M u s c l e ) = . 0 8 6 6 r a d s / 2mCi - 8 6 . 6 m r a d s / 2mCi 165 C a l c u l a t i o n o f Mean Dose t o t h e M u s c l e D E A 2 S ( r . | <- r 2 ) D M = E A wB s ( M u s c l e +• w h o l e B o d y ) + A M S ( M u s c 1 e <- M u s c l e ) 'X, + A L S ( M u s c l e +• L i v e r ) + A k , S ( M u s c 1 e <- K i d n e y ) = . 0 3 8 5 r a d s / 2mCi = 3 8 . 5 m r a d s ' / 2mCi 1 or> ( 2 ) ' " i - L a u r i c A c i d C a l c u l a t i o n o f t h e Mean Dose t o t h e K i d n e y s D = E A 2 S(r-! + r 2 ) D k = A wB ( K i d n e y s W n o 1 e B o d y ) + \ S ( K i d n e y K i d n e y ) + A^ S ( K i d n e y «- L i v e r ) + A^ S ( K i dney<--<- M u s c l e ) = . 1 9 9 8 r a d s / 2mCi = 1 9 9 . 8 m r a d s / 2mCi C a l c u l a t i o n o f t h e Mean Dose t o t h e L i v e r D L = AWB s ( L l v e r W h o l e B o d y ) + A^ S ( L i v e r <• L i v e r ) a, a. + A K S ( L i v e r K i d n e y ) + A^ S ( L i v e r <- M u s c l e ) . 1859 r a d s '••/ 2mCi = 1 8 5 . 9 m r a d s / 2mCi 166 C a l c u l a t i o n o f t h e Mean Dose t o t h e M u s c l e D M = AWB s ( M u s c 1 e W n o 1 e B o d v ) + A N | S ( M u s c 1 e *• M u s c l e ) + A^ S ( M u s c l e K i d n e y ) + S ( M u s c l e •«- L i v e r ) = . 0 5 2 0 7 r a d s / 2mCi = 5 2 . 0 7 m r a d s / 2mCi TABLE X X I V " The Mean A b s o r b e d Dose t o t h e W h o l e B o d y , K i d n e y s , L i v e r , a n d 123 1 2 3 M u s c l e U s i n g I - C a p r i c a n d I - L a u r i c A c i d s  Mean A b s o r b e d Dose ( m r a d s ) a W h o l e Body K i d n e y s L i v e r M u s c l e 123 I - C a p r i c A c i d 3 4 . 7 6 1 3 6 . 3 8 6 . 6 3 8 . 5 1 2 3 I - L a u r i c A c i d 4 1 . 7 3 1 9 9 . 8 1 8 5 . 9 5 2 . 0 7 a 2 m C i o f r a d i o i o d i n a t e d f a t t y a c i d a d m i n i s t e r e d . 123 The mean a b s o r b e d d o s e f o r t h e I - l a u r i c a c i d a p p e a r e d t o be 123 somewhat h i g h e r t h a n I - c a p r i c a c i d f r o m t h e d a t a r e c o r d e d f r o m t h e w h o l e b o d y d i s t r i b u t i o n s t u d i e s . The mean a b s o r b e d d o s e f o r t h e w h o l e 123 body was 3 4 . 7 6 m r a d / 2 m C i o r 1 7 . 3 8 m r a d / m C i f o r I - c a p r i c a c i d 123, a n d 4 1 . 7 3 m r a d / 2 m C i o r 2 0 . 8 7 m r a d / m C i f o r I - c a p r i c a c i d . , T h i s was c o m p a r a b l e t o t h e a b s o r b e d r a d i a t i o n d o s e o f 30 m r a d s / m C i t o t h e t o t a l 103 body c a l c u l a t e d f o r I - h e x a d e c e n o i c a c i d . ( P o e e t a l . , 1 9 7 6 b ) 167 C a l c u l a t i o n o f t h e Mean Dose, t o t h e H e a r t R a d i a t i o n d o s i m e t r y f o r t h e h e a r t was d i f f i c u l t t o c a l c u l a t e as ' S ' v a l u e s w e r e n o t r e a d i l y a v a i l a b l e . The a b s o r b e d d o s e f r a c t i o n s (j) f r o m t h e o t h e r o r g a n s t o t h e h e a r t w e r e a v a i l a b l e a l t h o u g h t h e c o n t r i b u t i o n f r o m t h e h e a r t t o t h e h e a r t was n o t a v a i l a b l e . U s i n g t h e f o r m u l a : D = A E A, A. M 1 1 t h e mean a b s o r b e d d o s e t o t h e h e a r t c a n be a p p r o x i m a t e d . From t h e d o s i m e t r y c a l c u l a t i o n s o f Poe e t a l . ( 1 9 7 6 b ) t h e Z A • ^ v a l u e f o r t h e h e a r t t o t h e h e a r t i s a p p r o x i m a t e l y . 1 7 3 4 . T h i s was b a s e d on t h e a s s u m p t i o n o f a 300 g h e a r t ( f o r n o n - p e n e t r a t i n g r a d i a t i o n o n l y ) a n d a m y o c a r d i a l b i o l o g i c a l h a l f - l i f e o f 30 m i n . O t h e r a s s u m p t i o n s w e r e made t h a t : K i d n e y mass = 310 g L i v e r mass = 1800 g M u s c l e mass = 4 8 , 4 8 0 g B o d y mass = 6 9 , 8 8 0 g T h e r e f o r e , t h e d o s e t o t h e h e a r t becomes D h e a r t = A H E A R T E ^ ^ ( H e a r t <- H e a r t ) + A U v e r E A . «>. ( H e a r t * - L i v e r ) M M h e a r t L i v e r A K i d n e y s E A i * i ( H e a r t ^ K i d n e y s ) - + A M U S C ] . E E A - ( H e a r t * - M u s c l e ) K i d n e y s M u s c l e A W h o l e body E A i * i ^ H e a r t * W h o 1 e B o d y ) -M W h o l e b o d y TABLE XXV Absorbed Dose F r a c t i o n s f o r the Heart Ei (MeV) " i A, ( g - r a d ) 1 ( i i C r b r ) • l * 2 * 3 .1590 .335 .2828 .00420 .00674 .00185 .1272 .134 .0363 .00420 .00674 .00185 .1544 .0153 ,0050 .00420 .00674 .00185 .1582 .0051 .0017 .00420 .00674 .00185 .2740 .0014 .0008 .00337 .00570 .00170 .3420 .0016 .0012 .00337 .00570 .00170 .4360 .0044 .0041 .00372 .00573 .00208 .5040 .0028 .0030 .00372 .00573 .00208 .5300 .020 .0226 .00372 .00573 .00208 .0271 .472 .0276 .00769 .00531 0.000 .0272 .242 .0140 •00769 .00531 0.000 .0310 .127 .0084 .00635 .00531 .000204 .0318 .0264 .0018 .00635 .00531 .000204 . 3 0 3 8 . 1 3 3 .0011 .00756 0.000 0.000 .0227 .0877 .0042 .00769 .00132 0.000 .0264 .0370 .0021 .00769 .00132 0.000 .0302 .006 .0004 .00635 .00531 .000204 .0029 . 9 2 2 .0057 .00756 0.000 0.000 . 0 0 0 8 2.18 .0037 .00756 0.000 0.000 .01151 .01668 .005230 1. C o n t r i b u t i o n from whole body t o h e a r t 2. C o n t r i b u t i o n from l i v e r t o heart 3 . C o n t r i b u t i o n from kidney to h e a r t 169 The a p p r o x i m a t e d E A . ^ f o r t h e m u s c l e t o t h e h e a r t i s . 0 9 6 9 6 , a s s u m i n g 4 8 , 4 8 0 g f o r m u s c l e . (1) 1 2 3 I - C a p r i c A c i d A s s u m i n g a maximum u p t a k e o f 1 . 5 % by t h e h e a r t . W = 2 0 - 7 4 ^C i - h D h e a r t = ' ° 2 5 8 9 r a d s / 2 m C i = . 0 1 2 9 5 r a d s / m C i ( 2 ) 1 2 3 I - L a u r i c A c i d The same a s s u m p t i o n s f o r m a s s e s o f t h e o r g a n s w e r e ; . m a d e . A maximum o f 2 . 1 2 % o f t h e i n j e c t e d d o s e was t a k e n up by t h e h e a r t . D h e a r t = ' 0 4 6 3 9 r a d s / 2 m C i = . 0 2 3 1 9 r a d / m C i .- The mean a b s o r b e d d o s e t o t h e h e a r t was c a l c u l a t e d t o be . 0 1 2 9 5 r a d / m C i f o r 1 2 3 I - c a p r i c a c i d a n d . 0 2 3 1 9 r a d / m C i f o r 1 2 3 I - l a u r i c a c i d . T h i s i s somewhat l o w e r t h a n t h e d o s i m e t r y c a l c u l a t i o n s o f Poe e t a l . ( 1 9 7 6 b ) i n w h i c h t h e y o b t a i n e d a v a l u e o f . 0 4 r a d / m C i f o r t h e h e a r t . T h i s l o w e r v a l u e c o u l d be due t o t h e f a c t t h a t we a s s u m e d t h e d i s t r i b u t i o n o f r a d i o i o d i n a t e d f a t t y a c i d s i n m i c e a l s o a p p l i e d t o h u m a n s . I n a d d i t i o n , t h e maximum m y o c a r d i a l u p t a k e f r o m o u r r e s u l t s Was 2 . 1 2 % c o m p a r e d t o an a s s u m e d m y o c a r d i a l u p t a k e o f 5% i n t h e s t u d i e s o f Poe e t a l . ( 1 9 7 6 b ) . ]69a V. SUMMARY AND CONCLUSIONS 170 1 0 - B r o m o c a p r i c a c i d , 1 2 - b r o m o l a u r i c a c i d , a n d 2 b r o m o t e t r a d e c a n o i c a c i d w e r e l a b e l e d by i n t e r n a l o g e n r e p l a c e m e n t a f f e c t e d by r e f l u x i n g w i t h N a I - 1 3 1 i n a c e t o n e . R a d i o c h e m i c a l p u r i t y was a s c e r t a i n e d by c h r o m a t o g r a p h y . P r e l i m i n a r y s c a n s a n d d i s t r i b u t i o n s t u d i e s s h o w e d t h a t 2 - i o d o t e t r a -d e c a n o i c a c i d was i n f e r i o r t o t h e t w o t e r m i n a l r a d i o i o d i n a t e d f a t t y a c i d s i n m y o c a r d i a l u p t a k e a n d t h u s was e x c l u d e d f r o m f u r t h e r s t u d i e s . T i s s u e d i s t r i b u t i o n s t u d i e s s h o w e d t h a t t h e h i g h e s t a c c u m u l a t i o n 131 o f r a d i o a c t i v i t y was i n t h e m u s c l e a n d t h e b l o o d f o r b o t h I - c a p r i c 131 a c i d a n d I - l a u r i c a c i d . O t h e r o r g a n s i n v e s t i g a t e d i n c l u d e d t h e h e a r t , l i v e r , l u n g , k i d n e y s , s p l e e n , s t o m a c h , i n t e s t i n e s , b o n e , a n d a d r e n a l s . When t h e r e s u l t s w e r e e x p r e s s e d as " p e r c e n t i n j e c t e d d o s e . p e r t o t a l o r g a n " , no o r g a n a p p e a r e d t o h a v e s p e c i a l a f f i n i t y t o i n c o r p o r a t e t h e r a d i o i o d i n a t e d f a t t y a c i d s . H o w e v e r , when t h e r e l a t i v e a c c u m u l a t i o n o f t h e r a d i o i o d i n a t e d f a t t y a c i d s w e r e e x p r e s s e d as " p e r c e n t i n j e c t e d d o s e p e r g r a m o r g a n " , t h e h e a r t s h o w e d t h e h i g h e s t u p t a k e o f t h e l a b e l e d f a t t y a c i d s f o r t h e f i r s t . 0 5 h o u r s , a f t e r w h i c h t h e r e was a d e c l i n e i n r a d i o a c t i v i t y . From t h e o b s e r -v a t i o n s o f t h e t i m e c o u r s e a n d t h e l o c a l i z a t i o n o f t h e l a b e l e d compounds w i t h i n t h e mouse b o d y , i t a p p e a r e d t h a t t h e o p t i m u m t i m e f o r m y o c a r d i a l i m a g i n g w o u l d be i m m e d i a t e l y a f t e r i n j e c t i o n o f t h e r a d i o i o d i n a t e d f a t t y a c i d s . The LDgQ o f s o d i u m b r o m o l a u r a t e was c a l c u l a t e d a f t e r i n t r a v e n o u s a d m i n i s t r a t i o n i n m i c e a n d f o u n d t o be 210 mg/kg ( 1 9 4 mg/kg - 2 2 8 m g / k g ) . The b r o m o c a p r i c a c i d was d i s s o l v e d i n a s o l v e n t s y s t e m s i m i l a r t o t h a t 1 7 1 o f N e m b u t a l U . S . P . The L D & 0 v a l u e s may n o t n e c e s s a r i l y r e f l e c t t h e t o x i c i t y o f t h e b r o m o c a p r i c a c i d s o l e l y . The L D ^ Q was f o u n d t o be 8 6 . 1 mg/kg ( 8 3 . 0 mg/kg - 8 9 - 3 m g / k g ) . The e x c r e t i o n o f t h e r a d i o a c t i v i t y a f t e r a d m i n i s t r a t i o n o f t h e r a d i o i o d i n a t e d f a t t y a c i d s was p r i m a r i l y by t h e k i d n e y s . W h o l e body c o u n t i n g r e v e a l e d a t r i e x p o n e n t i a l e x c r e t i o n c u r v e i n m i c e . 1 3 1 F o r I - c a p r i c a c i d , t h e e f f e c t i v e h a l f - l i v e s o f t h e s h o r t l i v e d c o m p o n e n t was . 9 0 h o u r s ( 3 6 . 7 % ) , t h e medium c o m p o n e n t was 3 . 9 1 h o u r s 1 O l ( 6 1 . 6 % ) , and t h e l o n g c o m p o n e n t was 7 4 . 9 h o u r s ( 1 4 . 5 % ) . F o r I - l a u r i c a c i d , t h e e f f e c t i v e h a l f - l i v e s o f t h e s h o r t l i v e d , c o m p o n e n t was 1 . 6 7 h o u r s ( 4 6 . 6 % ) , t h e medium c o m p o n e n t 7 . 6 8 h o u r s ( 3 8 . 4 % ) , and t h e l o n g c o m p o n e n t was 7 1 . 6 h o u r s ( 1 7 . 8 % ) . F o r b o t h t h e r a d i o i o d i n a t e d f a t t y a c i d s , t h e f i r s t as w e l l as t h e s e c o n d c o m p o n e n t p r e s u m a b l y r e p r e s e n t e d a d e c r e a s e i n t h e w h o l e b o d y r a d i o a c t i v i t y due p r i m a r i l y t o u r i n a r y e x c r e t i o n . The t h i r d c o m p o n e n t may r e p r e s e n t r a d i o a c t i v i t y t i g h t l y b o u n d t o some t i s s u e a n d s l o w l y r e l e a s e d . The r a d i o a c t i v i t y may be t h y r o i d a l I o d i d e - 1 3 1 o r p r o t e i n b o u n d i o d i d e . T h i s t h i r d c o m p o n e n t p r e s u m a b l y r e p r e s e n t s e l i m i n a t i o n by f e c a l e x c r e t i o n . 1 3 1 F o r I - c a p r i c a c i d , u r i n e c o l l e c t i o n s s h o w e d t h a t a t 1 0 and 2 4 h o u r s r e s p e c t i v e l y p o s t - i n j e c t i o n , 7 3 . 0 % a n d 8 2 . 4 % o f t h e i n j e c t e d a c t i v i t y h a d b e e n r e c o v e r e d . F e c a l e x c r e t i o n was f o u n d t o be 3 . 8 5 % a n d 8 . 8 8 % o f t h e i n j e c t e d d o s e a t 1 0 a n d 2 4 h o u r s r e s p e c t i v e l y 1 3 1 p o s t - i n j e c t i o n . F o r I - l a u r i c a c i d , 7 0 . 4 % a n d 7 8 . 9 % o f t h e i n j e c t e d d o s e was r e c o v e r e d i n t h e u r i n e a t 1 2 a n d 2 4 h o u r s r e s p e c t i v e l y . ' F e c a l r e c o v e r y was 7 . 3 3 % and 9 . 4 % o f t h e i n j e c t e d 172 d o e s e a t 12 a n d 24 h o u r s r e s p e c t i v e l y . C h r o m a t o g r a p h y o f t h e u r i n e s h o w e d t h a t t h e r a d i o a c t i v i t y was e x c r e t e d i n t h e f o r m o f t h e i o d i d e - 1 3 1 i o n . 7. U r i n a r y r e s u l t s o f b o t h r a d i o i o d i n a t e d f a t t y a c i d s r e v e a l e d an e f f e c t i v e h a l f - l i f e o f 4 . 8 h o u r s f o r t h e k i d n e y s . From t h i s , t h e b i o l o g i c a l h a l f - l i f e f o r t h e k i d n e y c a n be c a l c u l a t e d t o be 4 . 9 2 h o u r s . 131 131 8 . S e r i a l s c a n s w e r e p e r f o r m e d f o r I - c a p r i c a c i d , I - l a u r i c a c i d , N a I - 1 3 1 (6% H S A ) , and T h a l l i u m - 2 0 1 u s i n g t h e S e a r l e gamma c a m e r a . B e t t e r q u a l i t y s c a n s w o u l d h a v e b e e n p o s s i b l e w i t h t h e u s e o f I o d i n e - 1 2 3 as t h e r a d i o n u c l i d e , b a c k g r o u n d s u b t r a c t i o n f r o m t h e f i n a l i m a g e , a n d m a g n i f i c a t i o n o f t h e a r e a o f i n t e r e s t . 9 . T h e o r e t i c a l r a d i a t i o n d o s e s w e r e c a l c u l a t e d f r o m t h e r e s u l t s o f b o t h t h e d i s t r i b u t i o n a n d t h e e x c r e t i o n s t u d i e s i n m i c e . T h i s 123 d a t a was e x t r a p o l a t e d t o h u m a n s . F o r ; I - c a p r i c a c i d , t h e mean a b s o r b e d d o s e was c a l c u l a t e d t o be 3 4 . 7 6 m r a d s / 2 mCi f o r t h e w h o l e b o d y , 1 3 6 . 3 m r a d s / 2 mCi f o r t h e k i d n e y s , 8 6 . 6 m r a d s / 2 mCi f o r t h e l i v e r , 3 8 . 5 m r a d s / 2 mCi f o r t h e m u s c l e , and 2 5 . 8 9 m r a d s / 2 mCi f o r 1 23 t h e h e a r t . F o r I - l a u r i c a c i d , t h e mean a b s o r b e d d o s e was 4 1 . 7 3 m r a d s / 2 mCi f o r t h e w h o l e b o d y , 1 9 9 . 8 m r a d s / 2 mCi f o r t h e k i d n e y s , 1 8 5 . 9 m r a d s / 2 mCi f o r t h e l i v e r , 5 2 . 0 7 m r a d s / 2 mCi f o r t h e m u s c l e , a n d 4 6 . 3 9 m r a d s / 2 mCi f o r t h e h e a r t . The s c o p e o f t h i s i n v e s t i g a t i o n was t o e v a l u a t e t h e p o s s i b l e u s e 123 123 o f I - c a p r i c a c i d a n d I - l a u r i c a c i d as m y o c a r d i a l s c a n n i n g a g e n t s . H o w e v e r , due t o t h e p r o b l e m s e n c o u n t e r e d w i t h t h e p r o d u c t i o n o f I o d i n e - 1 2 3 , 173 t h e e x p e r i m e n t s w e r e c a r r i e d o u t u s i n g I o d i n e - 1 3 1 . The p r e l i m i n a r y d i s t r i b u t i o n s t u d i e s r e v e a l e d t h a t r a d i o i o d i n a t e d f a t t y a c i d s a r e i n d e e d t a k e n up by t h e h e a r t . . The t o x i c i t y s t u d i e s s h o w e d t h a t c a r e m u s t be t a k e n t o e n s u r e t h a t a minimum amount o f u n l a b e l e d f a t t y a c i d i s a d m i n i s t e r e d w i t h t h e r a d i o i o d i n a t e d f a t t y a c i d s . The e x c r e t i o n s t u d y showed t h a t t h e r a d i o a c t i v e l a b e l was r e m o v e d f r o m t h e f a t t y a c i d a n d was p r i m a r i l y e x c r e t e d a s t h e i o n i n t h e u r i n e . The r a d i a t i o n d o s e s c a l c u l a t e d showed t h a t m i l l i c u r i e q u a n t i t i e s o f I o d i n e - 1 2 3 l a b e l e d compounds c o u l d be a d m i n i s t e r e d a n d s t i l l be w i t h i n t h e p e r m i s s i b l e r a d i a t i o n e x p o s u r e . 131 131 The I - c a p r i c a c i d i a n d I - l a u r i c a c i d s c a n s w e r e somewhat d i s a p p o i n t i n g i n t h a t t h e h e a r t i m a g e was d i f f i c u l t t o d i f f e r e n t i a t e f r o m t h e l i v e r i m a g e . I t was r e a l i z e d t h a t t h e f a t t y a c i d a n a l o g s u s e d i n t h i s i n v e s t i g a t i o n w e r e n o t t h e f a t t y a c i d s o f c h o i c e . H o w e v e r , i t was f e l t t h a t a l e n g t h y s y n t h e s i s p r o c e d u r e t o o b t a i n a more s u i t a b l e f a t t y a c i d was n o t w i t h i n t h e s c o p e o f t h i s s t u d y . I n p e r f o r m i n g t h e i n v e s t i g a t i o n , t h e n e c e s s a r y p r o t o c o l f o r t h e d e v e l o p m e n t o f a new r a d i o p h a r m a c e u t i c a l was f o l l o w e d . I f more s u i t a b l e t e r m i n a l b r o m i n a t e d f a t t y a c i d s s h o u l d become c o m m e r c i a l l y a v a i l a b l e i n t h e n e a r f u t u r e , t h e same e x p e r i m e n t a l p r o c e d u r e s c o u l d be f o l l o w e d t o e v a l u a t e t h e p o s s i b l e u s e o f t h e m a s m y o c a r d i a l s c a n n i n g a g e n t s . ]73a BIBLIOGRAPHY 174 B I B L I O G R A P H Y A h m a d , M . , D u b i e l , J . P . , V e r d o n , T . A . , and M a r t i n , R . H . : T e c h n e t i u m -99m s t a n n o u s p y r o p h o s p h a t e m y o c a r d i a l i m a g i n g i n p a t i e n t s w i t h a n d w i t h o u t l e f t v e n t r i c u l a r a n e u r y s m . C i r c u l a t i o n 5 3 : 8 3 3 , 1 9 7 6 . 131 A n g h i l e r i , L . J . : A new m e t h o d f o r t h e p r e p a r a t i o n o f l a b e l e d I o l e i c a c i d - 1 a n d t r i o l e i n - 1 . I n t . J . A p p l . R a d i a t . , . I s o t 1 6 : 5 3 , 1 9 6 5 . A n t h o n y , G . J . a n d L a n d a u , B . R . : R e l a t i v e c o n t r i b u t i o n s o f a - , g - , a n d w - o x i d a t i v e p a t h w a y s t o i n v i t r o f a t t y a c i d o x i d a t i o n i n r a t l i v e r . J . L i p i d R e s . 9 : 2 6 7 , 1 9 6 8 . B a l a z , T . : M e a s u r e m e n t o f a c u t e t o x i c i t y . I n M e t h o d s i n T o x i c o l o g y , P a g e t , G . E . e d . , F . A . D a v i s C o . , P h i l a d e l p h i a , P . A . , 1 9 7 0 , p . 4 9 . B a l l a r d , F . B . D a n f o r t h , W . H . , N a e g l e , S . , and B i n g , R . J . : M y o c a r d i a l m e t a b o l i s m o f f a t t y a c i d s . J . C l i n . I n v e s t . 3 9 : 7 1 7 , 1 9 6 0 . B a l l o u , G . A . , B o y e r , R . D . , and L u c k , J . M . 5 . : The e l e c t r o p h o r e t i c m o b i l i t y o f human s e r u m a l b u m i n as a f f e c t e d by l o w e r f a t t y a c i d s a l t s . J . B i o l . Chem. 1 5 9 : 1 1 1 , 1 9 4 5 . B e i e r w a l t e s , W . H . , I c e , R . D . , S h a w , M . J . , a n d R y o , U . Y . : M y o c a r d i a l u p t a k e o f l a b e l e d o l e i c and l i n o l e i c a c i d . J . N u c l . M e d . 1 6 : 8 4 2 , 1 9 7 5 / B e n n e t t , K . R . , S m i t h , R . O . , L e h a n , P . H . , a n d H e l l e m s , H . K . : C o r r e l a t i o n o f m y o c a r d i a l 42K u p t a k e w i t h c o r o n a r y a r t e r i o g r a p h y . R a d i o l o g y 1 0 2 : 1 1 7 , 1 9 7 2 . B e r m a n , D . S . , A m s t e r d a m , E . A . , H i n e s , H . H . , S a l e l , A . F . B a i l e y , G . B . , D e n a r d o , G . L . , a n d M a s o n , D . 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I n C a r d i o v a s c u l a r N u c l e a r M e d i c i n e . S t r a u s s , H . W . , P i t t , B . , a n d J a m e s , A . E . e d . , C V . M o s b y Company S t . L o u i s , 1 9 7 4 , p . 1 8 1 . Z a r e t , B . L . , S t r a u s s , H . W . , M a r t i n , N . D . , W e l l s , H . P . J r , a n d F l a m m , M . D . J r . : N o n i n v a s i v e r e g i o n a l m y o c a r d i a l p e r f u s i o n w i t h r a d i o a c t i v e p o t a s s i u m : s t u d y o f p a t i e n t s . a t r e s t , w i t h e x e r c i s e a n d d u r i n g a n g i n a p e c t o r i s , N. E n g . J . M e d . 2 8 8 : 8 0 9 , 1 9 7 3 a . Z a r e t , B . L . , S t e n s o n , R . E . , M a r t i n , N . D . , S t r a u s s , H . W . , W e l l s , H . P . J r . M c G o w a n , R . L . a n d F l a m m , M . D . : P o t a s s i u m - 4 3 m y o c a r d i a l p e r f u s i o n s c a n n i n g f o r t h e n o n i n v a s i v e e v a l u a t i o n o f p a t i e n t s w i t h f a l s e p o s i t i v e e x e r c i s e t e s t s . C i r c u l a t i o n 4 8 : 1 2 3 4 , 1 9 7 3 b . Z w e i m a n , F . G . , H o l m a n , B . D . , O ' K e e f e , A . , and I d o i n e , J . : S e l e c t i v e u p t a k e o f 9 9 m T c - c o m p l e x e s a n d 67Ga i n a c u t e l y i n f a r c t e d m y o c a r d i u m . J . N u c l . M e d . 1 6 : 9 7 5 , 1 9 7 5 . 

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